Pharmaceutical dosage form for application to mucous membranes

ABSTRACT

The present invention relates to a pharmaceutical dosage form for application to a mucous membrane, in particular to a buccal, intestinal, rectal or vaginal mucous membrane, comprising at least one sheet like, in particular film shaped, foil shaped or wafer shaped preparation comprising the active pharmaceutical ingredient, a release mechanism, and a trigger mechanism, wherein the trigger mechanism is adapted to trigger, at a predetermined site of action, in particular of the gastrointestinal tract, of the rectum or of the vagina, the release of the sheet like preparation by the release mechanism.

The present invention relates to a pharmaceutical dosage form forapplication on a mucous membrane, in particular buccal, intestinal,rectal or vaginal mucosa.

The pharmaceutical dosage form is designed such that it comprises atleast one sheet like, in particular film shaped, foil shaped or wafershaped preparation comprising the active pharmaceutical ingredient, arelease mechanism, and a trigger mechanism, wherein the triggermechanism is adapted to trigger, at a predetermined site of action, inparticular of the gastrointestinal tract, of the rectum or of thevagina, the release of the sheet like preparation by the releasemechanism.

Thereby, inter alia, the bioavailability of the active pharmaceuticalingredient is advantageously increased by pressing the film shaped, foilshaped or wafer shaped preparation against the mucous membrane at theapplication site and thus achieving a controlled contact, a rapid uptakeof the drug through the mucous membrane into the blood and thereby anincrease in the bioavailability.

Especially the bioavailability is a pharmacological measure which is ofgreat importance for the applicability of an active pharmaceuticalingredient and a dosage form comprising such an active pharmaceuticalingredient. Generally, the bioavailability indicates how rapidly and towhat extent the active pharmaceutical ingredient is taken uprespectively reabsorbed and is available at the site of action. Fordrugs that are administered intravenously the bioavailability is 100% bydefinition. The bioavailability observed after oral administration isgenerally called oral bioavailability.

Numerous drugs are in particular unsuitable for oral administration,since they show a too small bioavailability and/or highly variableintra-individual plasma levels. Possible causes for this are thedegeneration or deactivation of the drug by digestive secretions andenzymes, dilution effects by intestinal fluids, poor resorbability, ahigh first pass effect and a very short length of stay at the absorptionwindow. Among these drugs are, for example, proteins and peptides suchas Insulin, Buserelin, Oesmopressin, Calcitonin, and Estrogen as well asbiotechnologically produced drugs such as antibodies, e.g. Rituximab.

There are numerous efforts to study the properties of various mucousmembranes of mammals, especially humans, and to improve thebioavailability of active pharmaceutical ingredients. The particularfocus here are the properties of different mammalian, especially human,mucous membranes with respect to permeability for and influence of thedrug absorption.

These study results suggest that the permeability of mucous membranesfor different drugs increases in the following order: intestinalmucosa<colonic mucosa<buccal mucosa—vaginal mucosa (Alam, M. A. et al.,“Everted gut sac model as a tool in pharmaceutical research: limitationsand applications”, Journal of Pharmacy and Pharmacology, 2011, Vol. 64,pages 326-336; Berginc, K. et al., “Development and Evaluation of an InVitro Vaginal Model for Assessment of Drug's BiopharmaceuticalProperties: Curcumin”, AAPS PharmSciTech, Vol. 13, No. 4, 2012, pages1045-1053; van der Bijl, P. et al., “Comparative in vitro permeabilityof human vaginal, small intestinal and colonic mucosa”, InternationalJournal of Pharmaceutics, 2003, Vol. 261, pages 147-152; van der Bijl,P. et al., “Penetration of human vaginal and buccal mucosa by 4.4-kd and12-kd fluorescein-isothiocyanatelabeled dextrans”, Oral surgery oralmedicine oral pathology, 1998, Vol. 85, No. 6, pages 686-691; Hosoya, K.et al., “The structural Barrier of absorptive Mucosae: Site Differenceof the Permeability of Fluorescein labeled Dextran in Rabbits”,Biopharmaceutics & Drug Disposition, 1993, Vol. 14, pages 685-696).

Furthermore, research results show that the concentrated application ofan active pharmaceutical ingredient directly on the mucous membrane mayincrease its bioavailability compared to the administration of asolution or pill (Gupta. V. et al. “Mucoadhesive intestinal devices fororal delivery of salmon calcitonin”, Journal of Controlled Release,2013, Vol. 172, Issue 3, pages 753-762; Teutonico, D. et al.“Concentration and surface of absorption: Concepts and applications togastrointestinal patch delivery”, International Journal ofPharmaceutics, 2011, Vol. 413, pages 87-92).

Such a concentrated application of an active pharmaceutical ingredientdirectly onto the mucous membrane can be achieved with dosage formswhich contain the active pharmaceutical ingredient in a sheet like, inparticular film shaped, foil shaped or wafer shaped preparation, inparticular as a so-called wafer. Drawbacks of conventional wafers are,particularly, that known wafers dissolve partially or completely beforethe site of action and in particular for e.g. intestinal, rectal orvaginal wafers no contact with the mucous membrane can be guaranteed.Moreover, for e.g. intestinal, rectal and vaginal multilayered wafers nocontact with the correct site of the wafer and in particular nosufficiently long contact with the mucous membrane can be guaranteed.

It is an object of the present invention to provide a pharmaceuticaldosage form that overcomes the aforementioned drawbacks.

It is a further object of the present invention to provide apharmaceutical dosage form that enhances the bioavailability of activepharmaceutical ingredients contained in dosage forms which areadministered, in particular orally, vaginally or rectally.

It is yet a further object of the present invention to provide apharmaceutical dosage form, in particular a dosage form containing theactive pharmaceutical ingredient in a sheet like, in particular filmshaped, foil shaped or wafer shaped, preparation, preferably a wafer, inwhich a release of the active pharmaceutical ingredient at itspredetermined site of action is achieved and the amount of the activepharmaceutical ingredient available for resorption is increased, and/oran enhanced bioavailability and/or an enhanced rate of resorption isachieved.

In particular, it is an object of the present invention to provide arapidly releasing dosage form with a systemic effect. Finally, it is yeta further object of the invention to provide a dosage form that makes itpossible to apply active pharmaceutical ingredients, which cannot beadministered orally due to poor bioavailability, at a predetermined siteof action.

Especially, the present invention relates to a pharmaceutical dosageform for the application, preferably to an upper gastrointestinal tractsuch as throat, esophagus, cardia and/or stomach, and particularly tothe respective mucous membranes, that enables a local drug therapyand/or diagnostic investigation. Local diseases, in particular diseasesof the esophagus, can be treated with local acting drugs. However,generally current pharmaceutical dosage forms or application systemsoften do not target the specific diseased location; particularly they donot target the esophagus and/or its mucous membrane. Therefore,generally a large amount of the applied drug, particularly the activepharmaceutical ingredient, is absorbed systemically, which may causeside effects, in particular adverse reactions. In particular, it istherefore an object of the present invention to improve the localapplication of a drug, particularly an active pharmaceutical ingredient.Preferably, certain embodiments according to the present inventionspecifically achieve and/or only aim for this object of the presentinvention. Moreover, certain embodiments according to the presentinvention may achieve further objects of the present invention.Furthermore, certain embodiments of the present invention may have theobject to increase the bioavailability of an active pharmaceuticalingredient, locally deliver a useful substance, preferably a drug suchas an active pharmaceutical ingredient, treat the esophagus with a localacting drug and/or reduce side effects, in particular adverse reactions.

These and other objects of the invention are achieved by thesubject-matters of the present independent claims. Preferred embodimentsare subject of the dependent claims.

In particular, the present inventors make use in an advantageous mannerof the different permeability of various mucous membranes andparticularly their suitability for taking up various drugs, which areinter alia different in their molecular size and lipophilicity, toprovide a dosage form which allows a direct contact of the dosage formwith the mucous membrane after the release at a predetermined site ofaction.

In particular, the present invention is a pharmaceutical dosage form forthe application to mucous membrane, in particular to a buccal,intestinal, rectal or vaginal mucous membrane, and comprises at leastone sheet-like, in particular film-shaped, foil-shaped or wafer-shaped,preparation comprising the active pharmaceutical ingredient, a releasemechanism, and a trigger mechanism, wherein the trigger mechanism isadapted to trigger, at a predetermined site of action, in particular ofthe gastrointestinal tract, of the rectum or of the vagina, the releaseof the sheet-like preparation by the release mechanism.

Such a pharmaceutical dosage form according to the present inventionadvantageously allows improving the bioavailability of activepharmaceutical ingredients which are, in particular, contained inorally, vaginally, or rectally administered drugs, at a predeterminedsite of action. In addition, a release of the active pharmaceuticalingredient at its predetermined site of action is achieved by thepharmaceutical dosage form according to the present invention, whereby,in particular, the amount of the active pharmaceutical ingredientavailable for resorption can be increased as well as an increasedbioavailability and an increased resorption rate can be achieved.

In particular, this is achieved with the dosage form according to thepresent invention by the fact that a dosage form according to thepresent invention rapidly releases a sheet-like, in particularfilm-shaped, foil-shaped, or wafer-shaped, preparation comprising theactive pharmaceutical ingredient at a predetermined site of action witha systemic effect. Furthermore, the dosage form according to the presentinvention makes it possible to apply active pharmaceutical ingredients,which cannot be administered orally due to poor bioavailability, at apredetermined site of action.

Preferably the predetermined site of action is a mucous membrane, inparticular a buccal, intestinal, rectal or vaginal mucous membrane.

The pharmaceutical dosage form according to the invention thus allowsadvantageously a coming into contact, in particular a direct contact,with the predetermined site of action, in particular a mucous membrane,preferably a tissue absorbing the active pharmaceutical ingredient, andfurther advantageously an uptake of the drug into the blood. Theembodiment of the preparation comprising the active pharmaceuticalingredient is a sheet-like, in particular film-shaped, foil-shaped, orwafer-shaped preparation, in particular a so-called wafer,advantageously allows a release of the sheet-like preparation directlyonto a mucous membrane and a coming into contact, preferably coming intocontact with a relatively large surface area, at the predetermined siteof release, respectively site of action, whereupon the sheet-likepreparation can dissolve and release the active pharmaceuticalingredient. Such a coming into contact with the predetermined site ofaction advantageously allows an enhanced resorption of the activepharmaceutical ingredient, in particular a resorption of the activepharmaceutical ingredient to the mucous membrane, and the amount of theactive pharmaceutical ingredient available for resorption is therebyincreased. An increased bioavailability and/or an increased rate ofabsorption are thereby achieved, too.

Advantageously, an intestinal first-pass effect, i.e. a conversation ofthe active pharmaceutical ingredient during its first passage throughthe intestinal mucosa and possibly also through the liver, in particularof an orally administered dosage form, can be reduced by apharmaceutical dosage form according to the invention. Also, thedestruction of the active pharmaceutical ingredient before it reaches apredetermined site of action, e.g. by gastric acid and/or digestiveenzymes, can be advantageously reduced by a pharmaceutical dosage formaccording to the invention. The bioavailability of the activepharmaceutical ingredient is also advantageously increased by apharmaceutical dosage form according to the invention. A pharmaceuticaldosage form according to the invention particular advantageously allowsa reduction in dose maintaining approximately an equal therapeuticeffect, especially when compared to an application of a comparableconventional preparation, such as tablets, solutions, vaginal creams orsuppositories. Furthermore, a pharmaceutical dosage form according tothe invention advantageously allows a more accurate dosing of the activepharmaceutical ingredient as well as, where necessary, a reduction ofside effects, especially gastrointestinal side effects. Thepharmaceutical dosage form according to the invention furtheradvantageously allows a relatively simple and discrete handling as wellas a simple, particularly space-saving storage, wherein activepharmaceutical ingredients, which are comprised in the pharmaceuticaldosage form according to the invention, may have an improved stability,e.g. at high heat and humidity, in particular compared to solutions andgels.

The combination of a sheet-like preparation comprising the activepharmaceutical ingredient with a trigger mechanism and a releasemechanism realized by the present invention advantageously supports thepositive properties of a sheet-like preparation, particularly of awafer.

At a predetermined trigger site that is equal to or different from thesite of action the trigger mechanism triggers, e.g. by a key stimulus,the release mechanism and thereby the release of the sheet-likepreparation at the site of action. For example, a release mechanism willexpand and release the sheet-like preparation from the shell after thetrigger mechanism triggers the release mechanism, e.g. by contactingwith a key stimulus, for example depending on a change in pH value,pressure change or change of the fluid.

It is to be understood that the terms “site of action” and “applicationsite” as used herein are used interchangeably. In this regard, it isalso to be understood that “site of action” and “site of application”refer to the predetermined location of release of the preparation. Alsoit should be understood that an active pharmaceutical ingredient, whichis released at the “site of action” respectively “application site” mayexert its actual biochemical effect also at another location of the bodyor at another site of a biochemical cycle, e.g. at or aftermetabolization by the liver or reaching of an antibody at its targetmolecule. “Site of action” and “application site” as used herein do notnecessarily refer to the location of the biochemical, medical effect ofthe active pharmaceutical ingredient.

A pharmaceutical dosage form according to the present inventionparticular advantageously allows to protect the sheet-like preparation,in particular wafer, until it reaches the predetermined site of action,respectively application site, and to bring the sheet-like preparation,respectively the wafer, into contact with the predetermined site ofaction, in particular with a mucous membrane.

The pharmaceutical dosage form according to the present invention thusallows a targeted and complete adhesion to the predetermined site ofaction, respectively application site.

Further, this advantageously allows, inter alia, a prolongation of theresidence time at the absorption window, a displacement of fluids whichcould lead to an early detachment or dissolution of the sheet-likepreparation, particularly of the wafer.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the pharmaceutical dosage form further comprises ashell, wherein the shell contains the at least one sheet-like, inparticular film-shaped, foil-shaped, or wafer-shaped preparationcomprising the active pharmaceutical ingredient, and wherein preferablythe shell or the trigger mechanism comprises at least one aperturethrough which a fluid surrounding shell can come into contact with theinner space of the shell, wherein preferably the aperture is formed as aslit and/or the aperture is at least partially covered by the triggermechanism.

In particular, the shell of the preparation makes it possible to protectthe preparation by the shell against an unwanted release.

It is to be understood that a pharmaceutical dosage form according tothe invention may comprise a shell which contains at least one or moresheet-like preparations comprising the active pharmaceutical ingredient.The shell of the pharmaceutical dosage form according to the inventionand/or the dosage form itself further comprises a release mechanismand/or a trigger mechanism, wherein the trigger mechanism is adapted totrigger, at a predetermined site of action, in particular of thegastrointestinal tract, the release of the sheet-like preparation by therelease mechanism.

The release of the sheet-like preparation by the release mechanismpreferably takes place by at least partially moving out the preparationfrom at least a part of the shell.

An aperture in the shell allows in a particular advantageous manner anentry and/or a coming into contact of the fluid surrounding the shell,in particular of the fluid at the predetermined trigger site, e.g. afluid of the gastrointestinal tract, into respectively with the innerspace of the shell, in particular with the trigger mechanism and/orrelease mechanism which is located in the inner space of the shell.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the aperture is formed as a slit.

Such a slit may be embodied in different arrangements andconfigurations. For example, such a slit may be completely or partiallycircumferentially arranged at the shell. A slit that is completelycircumferentially arranged at the shell may be arranged such that theslit divides the shell into multiple, in particular two parts.

An aperture according to the present invention, in particular a slit,may also be arranged such that the sheet-like preparation is releasedfrom the shell through the aperture, in particular slit, upon release ofthe sheet-like preparation.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the aperture can be covered by the triggermechanism at least partially or completely.

Preferably the trigger mechanism covers the aperture at least partiallyor completely and thus allows to control, in particular to avoid theunwanted entry of fluid surrounding the shell.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the trigger mechanism is adapted to trigger therelease of the sheet like preparation by the release mechanism aftercontacting the pharmaceutical dosage form, in particular the triggermechanism, with a key stimulus.

The term “key stimulus” as used herein preferably refers to a change ofstate of the environment of the pharmaceutical dosage form according tothe invention which is suitable to trigger the trigger mechanism. Such achange of state of the environment, which is suitable to trigger thetrigger mechanism, is preferably a change that specifically occurs atthe predetermined site of action, e.g. in the gastrointestinal tract.Such a change of state of the environment may be a predetermined changeof a physical or chemical parameter of the environment of the dosageform. For example, at a predetermined site of action, preferably thegastrointestinal tract, a pressure or pH value that is specific for thepredetermined site of action or a composition of the environment, e.g. afluid at this site of action, that is specific for the predeterminedsite of action and in particular a change of it can serve as a keystimulus. E.g., a substantially lower pH value in the stomach ascompared to the usual pH value in the neck area, the oral cavity and thepharyngeal cavity, and in particular the change of the pH value from theneck area, the oral cavity and the pharyngeal cavity to the stomach, canserve as a key stimulus.

In particular, a fluid surrounding the dosage form at the predeterminedsite of action, e.g. gastric juice and/or another fluid of thegastrointestinal tract or vaginal fluid at the predetermined site ofaction, can comprise a predetermined pH value, a predetermined pressureor a predetermined composition respectively a change of it that issuitable to trigger the trigger mechanism.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the trigger mechanism is adapted to trigger therelease of the sheet like preparation by the release mechanism in a timecontrolled manner or immediately and/or the trigger mechanism is adaptedto release the sheet like preparation in a time controlled manner orimmediately after triggering of the trigger mechanism.

It is to be understood that a key stimulus that is adapted to triggerthe trigger mechanism at a predetermined trigger site may trigger thetrigger mechanism immediately or delayed, in particular time controlled,such that the trigger mechanism is adapted to trigger the release of thesheet like preparation by the release mechanism immediately or delayedsuch that the release occurs at the predetermined site of action, inparticular of the gastrointestinal tract, the vagina or the rectum. Therelease mechanism may also be configured in such a way that this releasemechanism can release the sheet like preparation immediately or delayed,in particular time controlled, at the predetermined site of action aftertriggering of the trigger mechanism.

In a particularly preferred embodiment of the pharmaceutical dosage formaccording to the present invention the trigger mechanism is adapted totrigger the release of the sheet like preparation by the releasemechanism immediately and/or relatively quickly and/or the releasemechanism is adapted to release the sheet like preparation immediatelyand/or relatively quickly after triggering the trigger mechanism.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention a key stimulus for triggering the triggermechanism involves a predetermined change of a physical or chemicalparameter of a fluid surrounding the dosage form, in particular at apredetermined trigger site, preferably of the gastrointestinal tract, ofthe rectum or of the vagina, wherein the key stimulus is preferablyselected from the group comprising a predetermined change of a pH value,a predetermined change of a pressure or a predetermined change of acomposition of a fluid surrounding the dosage form.

A key stimulus may be chosen such that it acts on the trigger mechanismimmediately at the predetermined site of action or already beforereaching the predetermined site of action at a predetermined triggersite that is different from the site of action. The key stimulus maytrigger the trigger mechanism immediately or delayed, it may inparticular trigger the trigger mechanism in time controlled manner. Therelease of the release mechanism may occur immediately or delayed, inparticular time controlled, after the triggering of the triggermechanism. In particular, a delayed triggering of the trigger mechanism,particularly a time controlled triggering of the trigger mechanism, canbe effected already at the removal of the dosage form from the packagingat the oral, rectal or vaginal intake of the dosage form, at the entryinto or exit from a predetermined compartment of the gastrointestinaltract, particularly of the rectum or of the vagina, by reaching apredetermined temperature, a pH value of the surrounding medium or atthe presence or absence of specific substances in the medium surroundingthe dosage form. Alternatively, the triggering of the trigger mechanismat the oral intake of the dosage form, at the entry into or the exitfrom a predetermined compartment of the gastrointestinal tract, of therectum or of the vagina, reaching a predetermined temperature or a pHvalue of the surrounding medium or the presence or absence of specificsubstances in the medium surrounding the dosage form may cause animmediate and/or relatively quick triggering of the trigger mechanism.

An immediate and/or relatively fast triggering of the trigger mechanismand/or an immediate and/or relatively rapid release of the releasemechanism maybe advantageous to bring the sheet like preparation intocontact with the site of action, in particular a mucous membrane, tomake a contact with a relatively large surface area and/or to provide anadvantageously increased surface area for the resorption of the activepharmaceutical ingredient at the site of action.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the trigger mechanism comprises a substance whosesolubility and/or solidity depends on at least physical and/or chemicalparameter of a fluid surrounding the dosage form, preferably selectedfrom the group comprising a pH value, a pressure or a composition of afluid surrounding the dosage form.

Preferably, the trigger mechanism is configured such that its physicaland/or chemical properties, e.g. its geometry, and/or of aggregation, ischanged by a key stimulus as described herein such that it can triggerthe release of the sheet like preparation by the release mechanism atthe predetermined site of action. The change of the properties of thetrigger mechanism may occur immediately or delayed, in particular timecontrolled, or dynamically following the key stimulus at thepredetermined trigger site.

The change of properties of the trigger mechanism may trigger animmediate or a delayed, in particular time controlled, or dynamicrelease of the sheet like preparation at the site of action. Under theterm “dynamic” as used herein it is preferably to be understood thatthere is an adapted response to the conditions that are present at thetrigger site and/or site of action, e.g. in the gastrointestinal tract.In other words, this refers to, for example, a principle which utilizesthat the intestinal contents remains acid whereby a trigger mechanism isnot (yet) triggered and thus a release mechanism does not release.

The term “time controlled” as used herein refers preferably to apredetermined time. For example, the release occurs after apredetermined period in case of a time controlled release.

It is also in the scope of the present invention that the release of therelease mechanism occurs immediately after the triggering of the triggermechanism. Alternatively, the release of the release mechanism may takeplace with a time delay which may be predetermined or which maydynamically change after the triggering of the trigger mechanism.

The change of the properties of the trigger mechanism may be caused byswelling, dissolution or changes in the solidity of the triggermechanism or of a part thereof.

In this context it is to be understood that the trigger mechanismimmediately or delayed, in particular time controlled or dynamically,e.g. after a predetermined period of time, triggers the release of thesheet like preparation by the release mechanism subsequently after thekey stimulus. For example, a trigger mechanism may unblock the mobilityof other elements, e.g. of the release mechanism, of the dosage form, orapertures which control the entry of a liquid surrounding a shell intothe inner space of the shell, e.g. of the gastrointestinal tract or ofthe vagina, subsequently after the key stimulus.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the trigger mechanism is a coating, whichpreferably at least partially covers an aperture and/or a releasemechanism or a part thereof.

In particular, in a preferred embodiment of the pharmaceutical dosageform according to the present invention the dosage form is provided atampon for the vaginal application, wherein the tampon is at leastpartially wrapped, coated and/or embraced by a sheet like, in particularfilm shaped, foil shaped or wafer shaped, preparation comprising theactive pharmaceutical ingredient. This tampon may advantageously serveas a trigger mechanism and e.g. swell when the tampon comes into contactwith the vaginal fluid as a key stimulus and may trigger by theresulting expansion of the circumference or diameter of the tampon therelease of the sheet like preparation by the release mechanism. Inparticular, such a release may establish a contact of the sheet like, inparticular film shaped, foil shaped or wafer shaped, preparationcomprising the active pharmaceutical ingredient with a predeterminedsite of action, in particular with a mucous membrane of the vagina,where the sheet like preparation rests against the vaginal mucousmembrane. Additionally or alternatively, such a tampon dosage form maybe at least partially coated by an (additional) trigger mechanism and/ora shell, in particular in form of a coating.

In particular, a trigger mechanism that covers an aperture and/or arelease mechanism or a part thereof, at least partially or completely,can be arranged and/or adapted such that the trigger mechanism loosens,dissolves or swells subsequently after the key stimulus, and thuspreferably triggers the release of the sheet like preparation.

In particular, an aperture respectively a slit can be sealedrespectively covered by a trigger mechanism embodied as a cladding insuch a way that an entry of fluid into the dosage form, preferably intoan inner space of a shell, is avoided, wherein such a trigger mechanismmay dissolve following a key stimulus at a predetermined trigger siteand/or may rupture upon the release of the sheet like preparation at apredetermined site of action. Regarding its mechanical properties such acladding is preferably adapted in such a way that it is not soluble inthe fluids surrounding the dosage form, e.g. of the vagina or of thegastrointestinal tract, thus retains its solidity and integrity.Admittedly, it is beneficial to construct the cladding such that therelease mechanism may develop enough force that the cladding ruptures atthe moment of release. If it would dissolve before the release, thusbefore the release mechanism develops enough force, e.g. by swelling orgas-formation, to unfold the preparation, then the fluid surrounding thedosage form, in particular in form of a capsule, might fill up thedosage form and jam the preparation. In particular, for a releasemechanism that is mechanically pretensioned, thus can develop the forceat any time, such a cladding can be soluble and therefore be the triggermechanism at the same time.

A trigger mechanism that at least partially seals or covers an aperturerespectively a slit may comprise a substance whose solubility depends ona key stimulus, in particular on a pH value of a surrounding medium. Forexample, a trigger mechanism can at least partially be made out of asubstance that is preferably selected from soluble polymer,hydroxypropyl methylcellulose phthalate or Eudragit.

It is to be understood that in particular the predetermined site ofaction of the release of the sheet like drug may be determined by a pHdependent change of solidity of the trigger mechanism and/or of asubstance that is comprised by the trigger mechanism.

It is also within the scope of the present invention that the mobilityof one or more elements of the dosage form, in particular a releasemechanism, relatively to each other is limited, in particular by atrigger mechanism, in particular in such a way that they remain fixed intheir initial position, and that in particular the release mechanismremains fixed in its initial position until the trigger mechanismtriggers.

It is to be understood that after the removal of the mobilityrestrictions, in particular after a property change and/or aconformational change, in particular a change in solidity of the triggermechanism, the positioning and/or the properties of one or more elementsof the dosage form, in particular of the release mechanism, changerelatively to each other in such a way that the release mechanism istriggered and the sheet like preparation is released be the releasemechanism.

Here, a release by the release mechanism may act upon the releasemechanism to release the sheet like preparation by a property changeand/or a conformational change, in particular of a change in solidity,of the release mechanism directly and/or a key stimulus, which is equalto or different from the key stimulus triggering the trigger mechanism,directly or by means of intermediate elements, that are selected fromthe group comprising e.g. pins, levers, springs, cable pulls, and pushrods or the like.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the dosage form, in particular the shell and/orthe trigger mechanism, comprises at least one predetermined breakingpoint.

The term “predetermined breaking point” as used herein is preferablyformed as a notch and/or perforation, preferably as notch, that changesits solidity related properties or properties related to something elseupon the exposure to a defined pressure.

Such a predetermined breaking point may be a part of the shell, inparticular of the capsule of the dosage form, a part of the releasemechanism or a part of the trigger mechanism.

In particular, such a predetermined breaking point, preferably apredetermined breaking point formed as a notch in the material, can bemade out of the same and/or out of another material out of which theelement comprising the predetermined breaking point is made. Forexample, a shell made out of hard gelatin can comprise a predeterminedbreaking point that is also formed out of hard gelatin; in particular, ashell made of hard gelatin can comprise a predetermined breaking pointin form of a notch of the hard gelatin.

It is within the scope of the knowledge or the person skilled in the artto determine the properties of a predetermined breaking point inrelation to the present invention, in particular its shatter propertiesby the nature and composition of the material, by the geometric form orby other parameters relating to the solidity.

For example, a predetermined breaking point relating to the presentinvention can be adapted and/or arranged such that the predeterminedbreaking point breaks and unblocks the mobility of other elements of thedosage form, in particular of the release mechanism and/or the triggermechanism, in particular apertures, that control the entry of fluid ofthe gastrointestinal tract into the dosage form, after an exposure of apredetermined pressure onto the dosage form, in particular onto thepredetermined breaking point.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the shell is formed out of a material that isessentially insoluble in a fluid which is present at the predeterminedtrigger site and/or predetermined site of action, in particular of thegastrointestinal tract. However, it is to be understood that such ashell may not just be insoluble at the predetermined trigger site butalso at other compartments that have to be passed to reach the triggersite and/or the site of action—in other words, on the complete paththereto.

In a preferred embodiment according to the present invention the shellconsists of or mainly consists of a material that is essentiallyinsoluble in a fluid which is present at the predetermined trigger siteand/or predetermined site of action, in particular of the rectum, of thevagina or of the gastrointestinal tract, preferably vaginal fluidrespectively gastric juice.

A material that is essentially insoluble in vaginal fluid respectivelygastric juice is preferably selected from the group comprising gastricjuice-resistant polymers, comprising acidic polymethacrylates such asmethacrylic acid:methyl methacrylate copolymers 1:1 (Eudragit L),methacrylic acid:methyl methacrylate copolymers 1:2 (Eudragit L),methacrylic acid:ethyl acrylate copolymer 1:1 (Eudragit L100-55), acidiccellulose derivatives such as hydroxypropyl methylcellulose acetatesuccinates (HPMCAS)-LF, -MF and/or -HF and cellulose acetate phthalate;acidic polymers based on vinyl alcohol such as polyvinyl acetate andvinyl acetate: Crotonic acid copolymer; zein, keratin, gluten, shellac,gelatin and alginic acid hardened with formaldehyde or glutaraldehyde.

In this context it is to be understood that a trigger mechanism, inparticular when such a trigger mechanism is embodied as a triggermechanism covering an aperture, is preferably made out of a materialthat is different to the shell, in particular out of a material that isessentially soluble in the fluid which is present at the predeterminedtrigger site and/or predetermined site of action, in particular of therectum, of the vagina or of the gastrointestinal tract, preferablyvaginal fluid respectively gastric juice.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the shell is made out of a material that isselected from the group comprising hard gelatin, polymers,thermoplastics as e.g. Eudragit or the like. In this regard, inparticular, materials can be beneficial that have been successfullytested, used and/or authorized already, e.g. for oral dosage forms.

In a further preferred embodiment of the pharmaceutical dosage formaccording to the present invention the shell consists of a material thatis selected from the group consisting of hard gelatin or polymers.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the shell is formed as a capsule.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the shell is made of a material which issubstantially insoluble in a fluid that is present at a predeterminedtrigger site or site of action, in particular of the gastrointestinaltract, preferably insoluble in gastric juice, wherein preferably theshell consists of a material which is selected from the group comprisingpolymers and/or hard gelatin.

Preferably, such an essentially insoluble material, in particularessentially insoluble in vaginal fluid respectively gastric juice, isselected from the group comprising gastric juice-resistant polymers,comprising acidic polymethacrylates such as methacrylic acid:methylmethacrylate copolymers 1:1 (Eudragit L), methacrylic acid:methylmethacrylate copolymers 1:2 (Eudragit L), methacrylic acid:ethylacrylate copolymer 1:1 (Eudragit L100-55), ammonio methacrylatecopolymers (e.g Eudragit RS), acidic cellulose derivatives such ashydroxypropyl methylcellulose acetate succinates (HPMCAS)-LF, -MF and/or-HF and cellulose acetate phthalate; acidic polymers based on vinylalcohol such as polyvinyl acetate and vinyl acetate:Crotonic acidcopolymer; zein, keratin, gluten, shellac, gelatin and alginic acidhardened with formaldehyde or glutaraldehyde. In particular, an ammoniomethacrylate copolymer is a material for the shell and/or for thetrigger mechanism.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the dosage form, in particular the shell and/orthe trigger mechanism, comprises a wick system, in particular acapillary system, that is adapted to direct fluid into the dosage formby capillary forces.

Such a wick system advantageously allows a, preferably predeterminedand/or controlled, entry of a fluid out of a tissue, in particular bycapillary forces, into the dosage form, in particular into an innerspace of the shell, by the capillary action of the wick system.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the dosage form, in particular the shell and/orthe trigger mechanism, comprises a wick system.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the release mechanism or a part thereof is anexpansion mechanism or comprises such an expansion mechanism.

The term “expansion mechanism” as used herein preferably refers to arelease mechanism for releasing the sheet like preparation that isadapted such that the sheet like preparation is expandable to apredetermined extent by the release mechanism, i.e. upon activation ofthe release mechanism the sheet like preparation is expanded to thispredetermined extent or extends to it, respectively. For example, thesheet like preparation, in particular a wafer, can be contained in theshell with a smaller spatial extent, e.g. lumped together, collapsed orfolded or brought into a smaller format in another way. A releasemechanism comprising an expansion mechanism or an expansion mechanismthat is realized as a release mechanism or as a part thereof ispreferably adapted to stretch respectively expand the sheet likepreparation, which is contained in the shell with a smaller spatialextent, to a predetermined size upon activation of the releasemechanism, in particular to spread out, to open or to unfold the sheetlike preparation or to bring it to a larger size in some other way.

This advantageously makes it possible to provide a relatively smalldosage form, in particular for rectal, oral or vaginal application,wherein the surface area of the sheet like preparation may beparticularly advantageously increased by an expansion or the sheet likepreparation, in particular for the active ingredient release at thepredetermined site of action. Additionally, also the surface of apredetermined site of action, in particular of the vagina, of the rectumor of the gastrointestinal tract, e.g. a mucous membrane or anintestinal wall, which is in contact with the sheet like preparation,may be increased.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the expansion mechanism is selected from the groupcomprising mechanical expansion system, gas driven expansion system,compressed foam or compressed tissue.

In a variation of the present invention the expansion mechanism is a gasdriven expansion system. Such a gas driven expansion system may comprisea pressure vessel which can be filled with a gas-forming agent.

Advantageously, a gas formed by a gas-forming agent may affect theexpansion of the sheet like preparation.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the release mechanism, in particular the expansionmechanism, comprises a gas-forming agent, that is preferably selectedfrom the group comprising sodium hydrogen carbonate and citric acid.

In a variant of the present invention the expansion system is amechanical expansion system. Such a mechanical expansion system may beconstructed as a joint or lever expander. In particular, such amechanical expansion system can be constructed such that the shellcomprises at least one joint or lever element that is preferablyarranged at a free end of the shell.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the expansion mechanism is adapted in such a waythat an expansion of the expansion mechanism results in an at leastpartially opening of the shell.

The at least partially opening of the shell advantageously allows therelease of the sheet like preparation at a predetermined site of action,in particular of the vagina, of the rectum or of the gastrointestinaltract.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the dosage form contains the preparation in afolded form and the expansion mechanism is adapted such that theexpansion of the expansion mechanism results in an unfolding of thepreparation.

Preferably, an unfolding of the preparation may also cause the openingof the shell, in particular capsule.

This advantageously allows to provide a relatively small dosage form,wherein in a particularly advantageous manner the surface area of thesheet like preparation like preparation may be increased by an unfoldingof the sheet like preparation, in particular to release the activepharmaceutical ingredient at a predetermined site of action, e.g. at amucous membrane.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the shell, preferably the wick system, if present,contains a gas-forming agent as release mechanism, in particular asexpansion mechanism, wherein the gas-forming agent is selected from thegroup comprising sodium hydrogen carbonate, citric acid, sodiumdihydrogen phosphate, pressurized gas, liquefied gas, and boilingliquid.

It is to be understood that preferably after an unblocking of anaperture by a trigger mechanism a wick system directs a fluidsurrounding the dosage form at a predetermined site of action, inparticular of the rectum, of the vagina or of the gastrointestinaltract, to a gas-forming agent, that thereupon forms a gas, e.g. carbondioxide by a chemical reaction, which expands respectively inflates agas tight shell that can be filled with a gas, in particular a balloon.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the preparation is formed as a gas tight shell, inparticular as a balloon, that can be filled with gas, and/or the dosageform contains the preparation in a folded form, preferably as a gastight shell that can be filled with a gas, in particular as a balloon.

It is to be understood that such a preparation formed as a gas tightshell that can be filled with gas, can be expanded, preferably by anexpansion mechanism, in particular by a gas driven expansion system, andcan be released at a predetermined site of action, in particular of thegastrointestinal tract. In a particularly advantageous manner the gastight shell, in particular balloon, that can be filled with a gas can beexpanded, in particular inflated, by introducing a gas into the gasfillable shell, in particular balloon. The thereby resulting pressurewithin the shell that can be filled with a gas, in particular balloon,preferably causes a close contact of the outer surface area of the gasfillable shell at the predetermined site of action, in particular of amucous membrane or intestinal wall. Additionally advantageously, themucous membrane or intestinal wall respectively a section of the mucousmembrane or intestinal wall may be slightly stretched such that anadvantageously increased surface area for the resorption of the activepharmaceutical ingredient is available.

In an alternative preferred embodiment of the pharmaceutical dosage formaccording to the present invention, the gas tight shell can be filledwith a gas, in particular balloon, comprises and/or the dosage form, inparticular the shell comprises a gas tight, gas fillable shell in afolded form, wherein the gas fillable shell, in particular balloon, iscoated with the sheet like preparation.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the gas-forming agent is arranged in a part of theshell that preferably is opposed to the part of the shell containing thepreparation and/or that is preferably facing the part of the shellcontaining the preparation.

Furthermore, the shell may be at least partially slit at such a part ofthe shell that is opposed to the part of the shell containing thepreparation and/or that is facing the part of the shell containing thepreparation, such that preferably the shell may be pushed open by thegas fillable shell, in particular balloon, upon expansion by fillingwith a gas, such that the shell that can be filled with a gas, inparticular balloon, may enter e.g. into the lumen of the rectum, of thevagina or of the gastrointestinal tract.

It is to be understood that in such an arrangement the shell may bepushed open at such a slit, preferably by the pressure developed bymeans of the introduced gas, and the shell that can be filled with agas, in particular the balloon, may be released.

In an preferred embodiment of the pharmaceutical dosage form accordingto the present invention the dosage form contains the preparation,preferably as a gas tight shell that can be filled with a gas, inparticular as a balloon, and the gas tight shell that can be filled witha gas comprises an aperture that is circumferentially attached at aninner border of the shell.

Preferably, the border of such an aperture is attached at the innerborder of the shell, such that gas out of the inner space of the shellcan stream into the gas tight shell that can be filled with a gas, inparticular into a balloon.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the shell is divided at its periphery.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the shell, in particular the expansion mechanism,preferably mechanical expansion system, comprises at least a first jointor lever element, preferably a hinge. Such a joint or lever element, inparticular a first joint or lever element, is advantageously arranged insuch a way that a shell, preferably a shell divided at its periphery, inparticular when it comprises several parts that a pivotally connectedwith such a joint of lever element may swing open or open up. Such ajoint or lever element, in particular a first joint or lever element,can be advantageously embodied, in particular, as a mechanical hinge, asa paper and/or by means of an incorporated material with elasticproperties. In particular, this joint or lever element can be formed asan integer part of the shell or can be connected (e.g. glued) to it.

The sheet like dosage form, in particular a wafer, may be contained inan inner space of the shell in a folded form and may be attached to aside, in particular to one or more edges of the, preferably multi-part,shell, that is opposed to the first joint or lever element, inparticular hinge, in such a way that turning or opening respectivelyswinging out or swinging open the shell or a part of the shell by meansof the first joint or lever element expands, in particular unfolds,and/or opens up the sheet like dosage form.

In order to assist such an expansion, in particular an unfolding, of thesheet like preparation like dosage form, the dosage form may containfurther elements.

In particular, such further elements can be arranged in such a way thata flip angle is advantageously enlarged such that the release of thesheet like preparation is enhanced. For this purpose, the shell maycomprise one or more further joint or lever elements or flexible partsadditionally to the first joint or lever element. In this context, it isto be understood that joint or lever elements may be adapted in such away that they can open up the preparation. Additionally oralternatively, further elements may be embodied that perform only thistask. Also sections of a multi-part shell may perform this task. Inother words, e.g. rods and bows may be provided that open up thepreparation and/or the dosage form, in particular to obtain a “tentlike” structure. Additionally or alternatively, also sponges orsomething similar may be used in an advantageous manner, wherein theycan open up the dosage form, however in particular, they cannotcontribute to the movement of the expansion or can contribute to it onlyto a small amount. Moreover, lever systems can be provided that realizea kind of a transmission stage that turn a small movement of the releasemechanism into a big movement of the whole dosage form.

In an embodiment with a shell that is divided at its periphery and/orcomprises a slit, the unwanted entry of fluid surrounding the shelland/or the dosage form into the shell, in particular into anintermediate space between two edges of the shell, may be advantageouslyavoided, when a slit and/or a slit occurring at the edges of two partsof a shell that is divided at its periphery, is at least partiallycovered by a sealing. In particular, a sealing can be made out of aflexible material that is e.g. waxen or gummy. In particular, it isbeneficial if possible unevenness at the edges of the shell iscompensated in this way. Alternatively or additionally, the slit and/ora slit, that is present at the edges of two parts of the shell which isdivided at its periphery, may also be sealed against unwanted entry offluid into the shell, wherein the fluid surrounds the shell and/or thedosage form. Further, alternatively or additionally, the slit and/or aslit occurring at the edges of two parts of the shell that is divided atits periphery may be completely or partially coated with a sealing, inparticular at an inner wall and/or outer wall of the shell, and/or maybe coated, at least partially with a trigger mechanism.

In this context, it is also within the scope of the present inventionthat a slit and/or a slit occurring at the edges of two parts of theshell that is divided at its periphery may be an aperture of the shelland/or of the trigger mechanism according to the different embodimentsof the present invention.

It is also within the scope of the present invention that a sealingand/or a trigger mechanism may be adapted in such a way that it rupturesupon the opening of the shell, in particular upon a flipping open of theshell, or that it dissolves beforehand.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the shell, in particular the expansion mechanism,preferably mechanical expansion system, comprises at least one springelement.

For example, such a spring element can be arranged in such a manner thatthe spring element effectuates the opening of the shell, in particular aflipping open of the shell. For this purpose, the spring element may beconstructed as a pretensioned spring element, in particular apretensioned spring, that applies a spring force to the shell or to apart thereof, wherein the spring force is sufficient to flip open theshell. A sealing and/or a trigger mechanism may counteract this flippingopen or opening of the shell effectuated by the spring. After dissolvingand/or rupture of the sealing and/or of the trigger mechanism, theopening, in particular flipping open, of the shell effectuated by thespring can take place. Additionally or alternatively, also furtherelements may be present, that transfer the movement of the spring, e.g.this function can also be achieved, as described herein, by a hinge, alever or a joint element.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the preparation comprises a swelling agent,wherein the swelling agent preferably is selected from the groupcomprising sponge and fibers.

Preferably, the swelling agent is arranged in the shell or in a partthereof. After a triggering of the trigger mechanism the swelling agentmay be arranged in such a manner that the preparation is released, inparticular unfolded, at a predetermined site of action, in particular ofthe gastrointestinal tract, and/or that the preparation is applied tothe predetermined site of action, e.g. a mucous membrane or anintestinal wall. For this purpose, it is preferred that the swellingagent forms a part or is a release mechanism, in particular expansionmechanism. Preferably, the swelling agent is a sponge or comprisesfibers, in particular compressed layers of fibers that preferablycomprise cellulose and/or consist of another suitable swellablematerial.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention, the shell comprises at least a first tube elementand, optionally, at least one further tube element.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention, the shell comprises a first tube element and atleast a second tube element, wherein the second tube element has asmaller tube diameter than the first tube element.

Preferably, the shell is formed by at least one first and/or at leastone first and at least one further tube element.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention a shell comprises a first tube element and atleast a second tube element, wherein the second tube element has smallertube diameter than the first tube element, and wherein the second tubeelement is at least partially arranged respectively inserted into thefirst tube element.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the shell comprises at least a first tube element,at least a second tube element, and a spring element, preferably acompression spring, wherein the spring element is arranged such that thespring element can move the at least one second tube elementlongitudinally relative to the first tube element.

It is to be understood that such a spring element, preferably within theshell, in particular in an inner space of the shell, preferably at leastwithin a tube element, is arranged in such a manner that this springelement applies a spring force to the shell, in particular to the atleast one first and/or to the at least one further spring element, thatis sufficient to move the second tube element longitudinally relative tothe first tube element. A sealing and/or a trigger mechanism maycounteract this unfolding or opening of the shell effectuated by thespring. After dissolving and/or rupture of the ceiling and/or thetrigger mechanism the spring driven displacement of the tube elementscan take place. Such a displacement of tube elements may result in anopening of the shell and/or release of the sheet like preparation. Inparticular, the drug can be applied onto the smaller tube and is thenpushed out of the shell, whereafter even more one or more further tubeswith preparations may be released. Alternatively, further appropriatesteps can be provided after moving out the tube that release thepreparation. In particular, the displacement may serve as a preparationof the release. In this context, it is also to be understood that thespecific configuration is selected depending on the desired final sizeof the dosage form and/or of the preparation.

Furthermore, the shell and/or a first and/or a further tube element maycomprise a mechanical stop that limits the displacement of the least onesecond tube element in the longitudinal direction relative to the firsttube element.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the shell comprises at least one joint or leverelement, that is preferably arranged at a free end of the shell.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the first joint or lever element is arranged at afree end of the shell.

In particular, a first joint or lever element may be arranged at a freeend of the shell, preferably at the free end of a first and/or of afurther tube element, that comprises a rotatably mounted lever.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the shell comprises at least a further joint orlever element.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the first joint or lever element and/or thefurther joint or lever element is formed as a joint, hinge and/or leveror comprises a joint, hinge and/or lever.

Preferably, a first joint or lever element and/or at least a furtherjoint or lever element can be aligned in such a way that they can carryout their joint or lever movement in different, preferably opposing,directions. A joint angle of a first joint or lever element and/or of aat least one further joint or lever element, in particular with regardto the shell, or a part thereof, in particular a tube element, may bechosen in such a manner and/or be adjustable, in particular swiveling,that an expansion of the sheet like preparation is achieved and/or ismade possible by a movement of the joint or lever. In particular, thediameter of the preparation can be enlargeable by a joint or levermovement.

It is also within the scope of the present invention that a joint orlever element, in particular a lever, may directly be hinged by a springelement or by intermediate elements.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the first joint or lever element and/or thefurther joint or lever element is at least partially covered by thetrigger mechanism.

For example, in an initial state of the dosage form a joint or leverelement or a plurality of joint or lever elements, in particular levers,can form the shell of the dosage form or at least a part thereof. Anunwanted entry of fluid at the edges of the joint or lever elementrespectively of the joint or lever elements into the dosage form may beavoided by sealings, form fit or coatings of the inner and/or outer wallof the joint or lever elements. Such sealings or coatings may ruptureupon opening of the shell, in particular upon an expansion of theexpansion system, and/or upon a joint or lever movement of the joint orlever elements or may dissolve before that.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the at least one first joint or lever elementand/or the at least one further joint or lever element is arranged insuch a way that a respective joint or lever element, in particular alever, of one end is arranged adjacent to a joint or lever element, inparticular lever, of the other end. Preferably, the at least one firstjoint or lever element and/or the at least one further joint or leverelement is pivotally and/or rotatably mounted at a first or further tubeelement. Preferably, the tube elements can comprise a slit in which atleast a part of the at least one first joint or lever element and/or ofthe at least one further joint or lever element can perform a slidingmovement—preferably driven by a spring—in particular in the direction ofthe end of the tube.

Preferably, the joint or lever elements of a first tube and the joint orlever elements of a second tube are arranged alternately in a closedstate of the dosage form such that preferably, in a closed state thejoint or lever elements of the first tube and the joint or leverelements of the second tube form a cladding or a shell.

In particular, in an arrangement, in which the joint or lever elementsof a first tube and the joint or lever elements of a second tube arearranged alternately in a closed state of the dosage form, the leverlength between the joint or lever elements of a first tube and the jointor lever elements of a second tube may extend over the whole length ofthe folded dosage form. It is to be understood that the maximum leverlength might be limited to half the length of the dosage form in a case,in which the lever or joint elements are arranged opposing each other,and that, in particular, the maximally achievable extension might besmaller.

Alternatively, the joint or lever elements of a first tube and the jointor lever elements of a second tube may also, at least partially, besuperimposed and/or overlap in a closed state, wherein the joint orlever elements are arranged such that the joint or lever elements do notobstruct each other upon a release according to the invention.

The arrangement of a first and/or of a second tube element and thearrangement of lever and joint elements can be chosen such, inparticular, that the lever and/or joint elements form a wreathstructure, which can be attached at the tube element that is facing theviewer,

when viewing the dosage form from the rear, thus looking at the smallestarea of the dosage form. In such an arrangement it would be beneficialif the joint or lever elements of a first tube and the joint or leverelements of a second tube are arranged alternately, preferably in aclosed state of the dosage form, so that, preferably in a closed statein which the joint or lever elements of the first tube and the joint orlever elements of the second tube form a shell and/or a cladding, thewreath structure at a first end of the dosage form, in particular at anend of the first tube element, and the wreath structure at a second endof the dosage form, in particular at an end of a second tube element,are offset in a rotationally symmetric manner. In this context it is tobe understood that preferably a joint or lever movement of the firstjoint or lever element and/or of the at least one further joint or leverelement causes an unfolding of a sheet like preparation that is in afolded form within the dosage form in an initial state, such that thesheet like preparation unfolds at a predetermined site of action in aparticularly advantageous manner, and preferably may contact a mucousmembrane or the intestinal wall.

A lever respectively lever element, as used herein, preferably refers toa mechanical force transformer, preferably comprising a rigid body thatis rotatably attached at a pivotal point. A hinge, as used herein,preferably refers to a movable connection of two planes, in particularof two parts of a shell, preferably of an edge. In particular, a hinge,preferably a connecting joint of one or more joint or lever elements, isarranged in such a manner that two parts of the shell are moveablyconnected, for example in order to obturate an inner space of the shellby a moveable construction element, in particular by parts of the shell.For the purpose a hinge is constructed in such a way that it can bearthe load of the moveable part and the force of the movement. A hinge, asused herein, may be constructed as a bearing with one degree of freedom.

Within the scope of the present invention a joint element, in particularlever, may be adapted such that a contact of the sheet like preparationwith a predetermined site of action, in particular with a mucousmembrane or intestinal wall is strengthened by connecting of joint orlever elements opposing each other, in particular levers, preferablycomprising at least one further flexible element.

It is to be understood that preferably a movement of a mechanicalexpansion system and/or joint or lever element, preferably embodied as apart of a release mechanism, is triggered by a trigger mechanism. Such atrigger mechanism may, for example, comprise a soluble polymer thatlocks the mechanical expansion system and/or joint or lever element(s),in particular levers, in its respectively their initial positions toeach other. At an intended contacting with a fluid at a predeterminedsite of action, in particular with a fluid of the gastrointestinaltract, the polymer may loosen and a spring element, if present, maytrigger and/or effectuate the movement of the mechanical expansionsystem and/or of the joint or lever element, in particular of the lever.Additionally or alternatively, a mechanical expansion system and/orjoint or lever element(s), in particular levers, may be pretensioned inan initial state and/or may at least partially form a spring elementsuch that the energy stored in a mechanical expansion system and/orjoint or lever element, in particular lever in this manner is releasedby triggering of the trigger mechanism and the mechanical expansionsystem and/or joint or lever element, in particular lever, moves asintended. For example, after triggering of the trigger mechanism thesheet like preparation can be released by pushing apart of tube elementsthat are at least partially engaged in a telescopic manner, for exampleby a spring element, by stretching and/or unfolding a sheet likepreparation that is contained in the shell in a folded form by theexpansion mechanism and/or joint or lever elements.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the sheet like preparation is a wafer.

In particular, the sheet like preparation of a dosage form according tothe invention can be formed as a so-called wafer. Such a wafer can fitto the irregular surface contour of a predetermined site of action, inparticular of a mucous membrane, for example of the intestinal, rectalor vaginal wall, after absorption of moisture. Additionally, a sheetlike preparation of a dosage form according to the invention may begellable or swellable.

In a preferred embodiment the sheet like preparation of a dosage formaccording to the invention is already flexible and stretchable before itis released out of the shell and can absorb a fluid entering the shell,e.g. from the gastrointestinal tract.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the thickness of the sheet like preparation is0.01 mm to 2 mm, preferably 0.03 mm to 1 mm, preferably 0.05 mm to 0.1mm.

In particular, this is beneficial to provide a sheet like preparationwith a relatively small thickness.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the sheet like preparation has an area between 0.5and 25 cm², preferably between 1 to 10 cm².

The sheet like preparation may have different shapes. In particular, asheet like preparation can have a round, triangular, quadrangular orpolygonal shape.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the sheet like, in particular film shaped, foilshaped or wafer shaped, preparation, that comprises the activepharmaceutical ingredient, contains an active pharmaceutical ingredientwith a drug content of 0.5 to 40% by weight, preferably 1 to 30% byweight, and most preferred 5 to 20% by weight.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the sheet like, in particular film shaped, foilshaped or wafer shaped, preparation comprising the active pharmaceuticalingredient has a single-layered or multi-layered structure out of asingle or multiple layers, wherein at least one (preferably first) layercontains an active pharmaceutical ingredient.

It is to be understood, that such a first layer containing the activepharmaceutical ingredient may be any layer of a multi-layeredpreparation with regard to its arrangement and that it is, inparticular, not limited to an outer, inner, bottom or upper layer.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the sheet like, in particular film shaped, foilshaped or wafer shaped, preparation, that comprises the activepharmaceutical ingredient, comprises a multi-layered structure ofmultiple layers, wherein at least a first layer contains a first activepharmaceutical ingredient and wherein at least a further layer containsat least a further active pharmaceutical ingredient.

It is also within the scope of the present invention that the activepharmaceutical ingredient contained in a first layer is equal to ordifferent from an active pharmaceutical ingredient contained in afurther layer. In particular, a sheet like preparation of a dosage formaccording to the invention can be embodied as a so-called combinationwafer and can contain a combination of active pharmaceutical ingredientsof at least two active pharmaceutical ingredients in one or more layersindividually or jointly.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the sheet like, in particular film shaped, foilshaped or wafer shaped, preparation comprising the active pharmaceuticalingredient comprises at least a first layer containing the activesubstance and/or a further layer containing the active substance,wherein the first layer containing the active substance and/or thefurther layer containing the active substance comprises a polymer,preferably a film forming polymer.

Such a layer comprising a polymer, preferably a film forming polymeradvantageously serves as an active ingredient reservoir, wherein such alayer can release the active pharmaceutical ingredient under the effectof a fluid.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the sheet like, in particular film shaped, foilshaped or wafer shaped, preparation comprising the active pharmaceuticalingredient comprises at least one first layer containing the activeingredient and/or a further layer containing the active ingredient,wherein the at least one first layer containing the active ingredient,and/or the further layer containing the active ingredient comprises apolymer, and wherein the polymer fraction in the at least one firstlayer containing the active substance and/or the further layercontaining the active substance, which contains the polymer, is at least10 to 90% by weight, preferably 20 to 70% by weight, and more preferred30 to 60% by weight.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the sheet like, in particular film shaped, foilshaped or wafer shaped, preparation comprising the active pharmaceuticalingredient comprises at least a first layer containing the activeingredient and/or a further layer containing the active ingredient,wherein the at least one first layer containing the active ingredientand/or the further layer containing the active ingredient is an adhesivelayer.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the at least one first layer containing the activeingredient and/or the further layer containing the active ingredientcomprises a polymer, preferably a film forming polymer, wherein thepolymer is a film forming polymer that is water dispersible and/ordecomposable and/or water disintegrable.

A polymer for a first layer containing an active substance and/or for afurther layer containing an active substance may, in particular, beselected from a group comprising polyvinyl alcohols,Polyvinylpyrrolidone, polyvinyl acetate, polyethylene glycol,polyethylene oxide polymers, polyurethanes, polyacrylic acids,polyacrylates, polymethacrylates, poly (methyl vinyl ether-maleic acidanhydrides), starch, starch derivates, natural gums, alginates, pectinsand gelatin, Pullulan, gel forming proteins, Chitosan, Agar-Agar,agarose, carrageenan, xanthan, tragacanth, dextran, and cellulose etherssuch as ethyl cellulose, hydroxyethyl cellulose, propyl cellulose,carboxymethyl cellulose, sodium-carboxy methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxypropyl ethyl cellulose,cellulose acetate, povidone and copovidone.

The polymers may be used individually or in a combination with eachother in order to manufacture a sheet like preparation for the dosageform according to the invention with the desired properties as adhesion,release or disintegration properties. In particular, a sheet likepreparation according to the invention can consist of a single polymerlayer. Also, a sheet like preparation for a dosage form according to theinvention may have a structure with two or multiple layers, when atleast one of the layers contains an active pharmaceutical ingredient. Ifmultiple layers contain the active pharmaceutical ingredient or theactive pharmaceutical ingredients, they may differ from each other intheir active ingredient content and in their combination of activeingredients, but also in their polymer composition and thus theiradhesion and/or decomposition properties.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the sheet like, in particular film shaped, foilshaped or wafer shaped, preparation comprising the active pharmaceuticalingredient comprises at least one first active ingredient free layer,that does not contain an active pharmaceutical ingredient.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the sheet like, in particular film shaped, foilshaped or wafer shaped, preparation comprising the active pharmaceuticalingredient comprises at least a further active ingredient free layerthat does not contain an active pharmaceutical ingredient.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the first active ingredient free layer and/or theat least one further active ingredient free layer is a water insolublelayer which preferably comprises water insoluble substances selectedfrom the group ethyl cellulose and/or combinations of ethyl cellulosewith other water insoluble substances, hydrophobic plasticizers,especially triethyl citrate, and/or dies and/or fragrances and/orflavorings.

In particular, the use of ethyl cellulose may be beneficial due to itsproperties comprising a good processability, biocompatibility, and waterinsolubility.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the first active ingredient free layer and/or theat least one further active ingredient free layer is an adhesive layerthat preferably comprises hydroxypropyl methylcellulose.

The adhesive layer may vary in its desired thickness. Additionally oralternatively, the adhesive layer may be a mucoadhesive polymer selectedfrom the group comprising cellulose derivates, starch and starchderivates, polyvinyl alcohol, polyethylene oxide, polyethylene,polypropylene, polyacrylic acid and polyacrylate derivates,Polyvinylpyrrolidone, Povidone, Copovidone, Sodium alginate, gelatin,Xanthan gum, Carrageenan, pectins, dextrans, lectins, Chitosan,Pullulan, and mixtures thereof.

The adhesive layer may vary in its desired thickness. Additionally oralternatively, the adhesive layer may comprise a solvent that isselected from the group comprising water, Ethanol, Methanol, Acetone,organic solvents, and mixtures thereof.

Furthermore, the adhesive layer may additionally contain additives suchas colorants, fragrances, flavoring agents, preservatives, antioxidants,penetration enhancers, solubilizers, disintegration accelerators, poreformers, lubricants, and mixtures thereof.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the sheet like preparation has a multi-layeredstructure, preferably with two or three layers, and comprises at leastone layer containing an active substance and at least one activeingredient free layer.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the sheet like preparation comprises amulti-layered structure, preferably with three layers, wherein a firstlayer containing an active ingredient and/or a further layer containingan active ingredient is arranged between a first active ingredient freelayer and/or a further active ingredient free layer, wherein,preferably, the first active ingredient free layer is a water insolublelayer, that preferably comprises ethyl cellulose, and the at least onefurther active ingredient free layer is an adhesive layer, thatpreferably comprises hydroxypropyl methylcellulose.

A drug according to the present invention, in particular a sheet likepreparation, may additionally contain one or more additives. Inparticular, the following substances are eligible as additives:lubricants, lubricants, glidants, binders, additional activeingredients, disintegrants, antioxidants, chelating agents, coatingagents, flow agents, preservatives, fillers, surfactants, plasticizers,and pigments. Furthermore, the additives may be selected from thefollowing group: pore formers, penetration enhancers, solubilizers,emulsifiers, comprising polyethoxylated sorbitan fatty acid esters,ethoxylated fatty alcohols, and lecithin; plasticizers, comprisingpolyethylene glycol, glycerol and other polyhydric alcohols, higheralcohols such as dodecanol, undecanol, or octanol, sorbitol, mannitoland other sugar alcohols, dexpanthenol and triglycerides; fillerscomprising highly disperse silicon dioxide, titanium dioxide, zincoxide, chalk and starch; colorants; sweetening and flavoring agents;wetting agents; preservatives; pH regulators and antioxidants;disintegration accelerators; permeation enhancers which improve theresorption of estradiol into the mucous membrane, for example, fattyacids and fatty acid esters, polyhydric alcohols such as propanediol,tocopherols or essential oils such as menthol.

The fraction of these additives may be up to 60% by weight relative tothe total weight of the sheet like preparation. Preferably, the fractionof the additives is between 5 and 40% by weight. By adding one or moreof said additives, the person skilled in the art can specificallyinfluence the chemical and physical properties of the film shaped drugcontaining the active ingredient such that, for example, a desiredflexibility, adhesivity, swellability or decomposability as well asdiffusion properties may be adjusted.

According to a preferred embodiment the pharmaceutical dosage form, inparticular the sheet like preparation, according to the invention isintended to enable a time delayed active ingredient release. The activepharmaceutical ingredient is preferably released over a period of 4hours, preferably over a period of 6 hours and most preferably over aperiod of 8 hours. In order to achieve a delayed active ingredientrelease in case of two-layered or multi-layered preparations, at leastone of the layers containing an active ingredient, in particular apolymer layer, has a delayed active ingredient release.

For a delayed active ingredient release the film shaped medicaments arepreferably formulated as slowly soluble or slowly disintegrating filmwhich are completely disintegrated or dissolved only after severalhours. Preferably, they are completely disintegrated or completelydissolved only after 4 hours, preferably only after 6 hours, and evenmost preferably only after 8 hours or even only after more than 24hours.

According to an alternative preferred embodiment the pharmaceuticaldosage form according to the invention, in particular the sheet likepreparation is a rapidly releasing dosage form which releases the activepharmaceutical ingredient within 1 hour, preferably within 30 minutes,and even most preferably within 5 minutes. For a rapid active ingredientrelease the film shaped preparation may preferably be formulated as afast dissolving or rapidly disintegrating film. The sheet likepreparation is adapted to essentially completely disintegrate, totransition to a gelatinous state or to dissolve preferably within a fewminutes after the release. Preferably, the sheet like preparation iscompletely disintegrated, transitioned into a gel state or completelydissolved within 1 hour, preferably within 30 minutes, more preferablywithin 15 minutes, and particularly most preferably within 5 minutes.

According to a preferred embodiment the film shaped medicamentsaccording to the invention are adhesive, in particular mucoadhesive. Anembodiment that comprises only an adhesive, in particular mucoadhesivesurface, is particularly preferred. Thereby, a sticking of the drugformulation to a predetermined site of action, in particular a mucousmembrane, during the application duration is achieved and the activepharmaceutical ingredient or the active pharmaceutical ingredients canbe resorbed directly at a predetermined site of action, in particularthrough a mucous membrane.

Furthermore, a sheet like preparation may comprise a layer at a sidethat is opposed to the adhesive, in particular mucoadhesive surface,wherein said layer is impermeable for the active pharmaceuticalingredient such that at the application at a predetermined site ofaction a directed active ingredient release can be achieved.

The pharmaceutical dosage form, in particular the sheet likepreparation, can be prepared by a person skilled in the art by basicallyknown methods, for example by coating of an inert support with a liquidcomposition which comprises the polymer(s), active pharmaceuticalingredient(s) and optionally additive(s) and solvent(s), by means ofe.g. a method involving a doctor blade, spray processors or extrusionprocessors. The thin film layer obtained in such a way is dried. For amulti-layered sheet like preparation one or more coatings may be appliedonto the existing film layer in the same manner or may be manufacturedseparately and then be subsequently laminated.

A pharmaceutical dosage form, in particular the shell and/or thesheet-like preparation, may further comprise at least one taste-maskingadditive. This advantageously allows the masking of a bitter or in someother way unpleasant tasting active pharmaceutical ingredient but mayalso be beneficial to accelerate the onset of effect of an activepharmaceutical ingredient. Taste-masking additives are known to theperson skilled in the art. Such a taste-masking additive may, inparticular, comprise a sugar alcohol selected from mannitol, sorbitol,xylitol, malitol, lactitol, erythritol, threitol, and isomalt as well assodium hydrogen carbonate.

An active pharmaceutical ingredient contained in a sheet-likepreparation of the pharmaceutical dosage form according to the inventionmay, in particular, be selected from the group comprising proteins andpeptides, in particular insulin, buserelin, oesmospressin, calcintoninand estrogen as well as biotechnologically manufactured drugs such asthe antibody rituximab. Here, it is to be understood that proteins andpeptides, in particular insulin, buserelin, oesmopressin, calciotoninand estrogen may display, under certain circumstances, a bad—inparticular a bad oral—bioavailability and thus are good candidates forthe application by means of the dosage form according to the presentinvention.

Substances from the following groups are particularly suited as activepharmaceutical ingredients: drugs acting on the skeleton and themuscles, drugs acting on the nervous system, hormones and drugs actingon the hormonal system, gynecologic acting drugs, drugs acting on thecardio-vascular system, drugs acting on the respiratory system, drugsacting on the gastrointestinal tract, diuretics, drugs acting on thesensory organs, dermatics, vitamins and micronutrients, peptide baseddrugs and proteins, analgesics, anti-infectives, and parasizides.

In particular, the sheet like preparation may comprise at least a firstregion and at least a second region, wherein the at least one firstregion comprises the active pharmaceutical ingredient. Preferably, theat least one second region comprises a further active pharmaceuticalingredient that is different from the active pharmaceutical ingredientof the at least one first region of the sheet like preparation. Alsopreferably, the at least one second region does not comprise the activepharmaceutical ingredient of the at least one first region of the sheetlike preparation. Alternatively and preferably, the at least one secondregion comprises the active pharmaceutical ingredient of the at leastone first region of the sheet like preparation with a concentration byarea, volume or mass that is different from the concentration of theactive pharmaceutical ingredient of the first region.

It is to be understood, that in this context active pharmaceuticalingredients may also refer to mixtures of active pharmaceuticalingredients and/or additives. Thus, the at least one second region ofthe sheet like preparation may comprise a mixture that differs from themixture of the at least one first region. In particular, the mixtures ofthe at least one first region and of the at least one second region maydiffer in the composition of active pharmaceutical ingredients and/oradditives as well as in the amount of the respective activepharmaceutical ingredients and/or additives.

In particular, this advantageously allows releasing different activepharmaceutical ingredients to different regions of the body, inparticular to different mucous membranes or to different regions of amucous membrane such as buccal, oral, esophageal, gastric, intestinal,rectal or vaginal mucosa, with a single pharmaceutical dosage form.Preferably, one active pharmaceutical ingredient or one mixture ofactive pharmaceutical ingredients can be applied to a first region ofthe vaginal mucosa that is closer to the cervix than a second region ofthe vaginal mucosa and another active pharmaceutical ingredient oranother mixture can be applied to said second region. Moreover, noactive pharmaceutical ingredients may be released to the first or thesecond region of the vaginal mucosa. Alternatively and preferably, thefirst region of the sheet like preparation may be in contact with anesophageal mucosa and the second region of the sheet like preparationmay be contact with a buccal mucosa. In this way, the esophageal mucosacan be treated with the active pharmaceutical ingredient while thebuccal mucosa is treated with another active pharmaceutical ingredient,not treated or an additive is released to the buccal mucosa. Inparticular, a flavoring agent and/or a local anesthetic may be released,particularly to increase or decrease the production of saliva and/or tomake the application of the pharmaceutical dosage form more pleasantand/or to suppress the urge to gag.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention, in which the sheet like preparation comprises atleast a first region and at least a second region, the second region maycomprise a further active pharmaceutical ingredient that counteracts theactive pharmaceutical ingredient of the first region. This may bebeneficial to suppress a systemic effect of the active pharmaceuticalingredient of the first region. In particular, a fluid that passes alongthe mucous membrane may pass, at first, the first region and then thesecond region, and therefore may, at first, take up the activepharmaceutical ingredient of the first region, which is thencounteracted, preferably neutralized, by the further activepharmaceutical ingredient of the second region. In particular, such anactive pharmaceutical ingredient counteracting the other pharmaceuticalingredient can be chosen from the following list: enzymes that breakdown active pharmaceutical ingredients such as esterases; ions that formcomplexes with the other active pharmaceutical ingredient such ascalcium, iron or magnesium; sympathomimetic drugs and sympatholyticdrugs; parasympathomimetic drugs and parasympatholytic drugs; antibodiesthat bind drugs; drugs to treat the side effects of the other activepharmaceutical ingredient without counteracting the effect of the otheractive pharmaceutical ingredient. Additionally or alternatively, thesheet like preparation may comprise, in a similar manner, a first layerwith the active pharmaceutical ingredient and a second layer with thefurther active pharmaceutical ingredient that counteracts the activepharmaceutical ingredient of the first layer. In this case, the abovementioned advantages may be achieved, wherein the effect of the activepharmaceutical ingredient of the first layer is directed in thedirection of the mucous membrane or away from it.

A preferred embodiment of the pharmaceutical dosage form according tothe present invention is adapted for the application to an uppergastrointestinal tract such as throat, esophagus, cardia and/or stomach,and particularly to the respective mucous membranes and/or preferably toa buccal and/or esophageal mucosa.

A preferred embodiment of the pharmaceutical dosage form according tothe present invention is adapted for the application to a nasopharyngealmucosa.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention, in particular a dosage form for the applicationto a buccal and/or esophageal mucosa, the shape of the dosage form or apart of the dosage form, in particular the shell, is such that can beswallowed.

In particular, a shell with the shape of a capsule can be swallowed.Preferably, the circumference of the capsule is shorter than 6 cm,preferably shorter than 3 cm, and preferably shorter than 2 cm, as wellas longer than 0.2 cm, preferably longer than 0.5 cm, and preferablylonger than 1 cm. Preferably, the longitudinal axis of the capsule isshorter than 5 cm, preferably shorter than 3 cm, and preferably shorterthan 2 cm, as well as longer than 0.5 cm, preferably longer than 1 cm,and preferably longer than 1.5 cm. In particular, the shell may have ashape according to a standard capsule form such as 00, 0, 1 or 3, whichhave a length along the longitudinal axis between 16.1 mm and 23.5 mmand a circumference between 17.9 mm and 26.7 mm. In a similar manner thepharmaceutical dosage form or the part of the pharmaceutical dosage formto be swallowed may be shaped. Furthermore, a smooth and/or glidablesurface of the shell, the dosage form or the part of the dosage form maybe beneficial to facilitate the swallowing.

This advantageously allows an oral administration of the pharmaceuticaldosage form according to the invention. In particular, only the dosageform or the part of the dosage form, preferably the shell, with thesuitable shape is swallowed. In this context it is to be understood,that parts of the dosage form may be adapted to be swallowed while otherparts of the dosage form may not be adapted to be swallowed.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention, in particular a dosage form for the applicationto a buccal and/or esophageal mucosa, a nasopharyngeal mucosa, agastrointestinal mucosa, a rectal mucosa or a vaginal mucosa, the sheetlike preparation comprises at least one active pharmaceutical ingredientselected from the group: diagnostics substances such as dyes or stains,analgesics, preferably NSAIDs, such as ibuprofen or flurbiprofen; localanesthetics such as benzocaine, butamben, dibucaine, lidocaine,oxybuprocaine or novocaine; antibiotics such as penicillin, amoxicillinor vancomycin; antiseptics such as 2,4-dichlorobenzyl alcohol,amylmetacresol or cetylpyridinium chloride; steroids such ascorticosteroids, glucocorticoids, fluticasone, budesonide, clocortolone,perdesonide, hydrocortisone, clobetasonbutyrate, flumetason,flupredniden, hydrocortisone aceponate, hydrocortisone buteprate,hydrocortisone-17-butyrate, triamcinolonacetonid, amcinoid,betamethason-17,21-dipropionate, betamethason-17-valerate,desoximetasone, diflucortolon-21-valerate, fluocinolonacetonid,fluocinonid, fluticason-17-propionate, methylprednisolone aceponate,mometasonfuroat, pednicarbat or clobetasol-17-propionate; parasizides,which are also called parasiticides, such as mebendazole, albendazole,tiabendazole, diethylcarbamazine, diaminodiphenyl sulfone, benznidazole,ivermectin, pyrantel, praziquantel; fungicides such as nystatin,imidazole, triazole, thiazole, clotrimazole, ketoconazole or undecylenicacid; hexamethyl pararosaniline chloride, Amphotericin B, botulinumtoxin, sucralfat, nitric oxide or nitric oxide forming agents such asisosorbide dinitrate or nitroglycerine, furanocoumarins, benzoic acid,citric acid, lactic acid, pH buffers, antacids, calcium carbonate,magnesium carbonate or aluminum carbonate. Additionally oralternatively, the sheet like preparation particularly can comprise aninflammation regulator such as montelukast, interleukin receptors orinterleukin antibodies. Additionally or alternatively, the sheetlikepreparation particularly can comprise beclomethasone dipropionate,budesonide or ciclesonide, which are particularly beneficial for asthmatherapy. Additionally or alternatively, the sheetlike preparationparticularly can comprise mesalazine, sulfasalazine or olsalazine, whichare particularly beneficial for treating inflammatory bowel disease.

In particular, the sheet like preparation comprising a specific activepharmaceutical ingredient advantageously allows, preferably locally,treating a respective disease or infection. Thus, a specific activepharmaceutical ingredient may be applied to a respective applicationsite, in particular a mucosa, and the local concentration and/or thetherapeutic effect may be increased and/or side effects, in particularadverse reactions, may be reduced compared to a systemic application. Inthis context it is to be understood, that besides the local effect alsoa systemic effect may be possible, preferably by the uptake of theactive pharmaceutical ingredient through the mucous membrane into thebody. Moreover, in a preferred embodiment the sheet like preparation maycomprise different active pharmaceutical ingredients, wherein at leastone active pharmaceutical ingredient is chosen such that it remains, atleast essentially, localized at and/or within the mucous membrane whileat least another active pharmaceutical ingredient is chosen such that itenters the body through the mucous membrane, thus in particular causinga systemic effect.

A preferred embodiment of the pharmaceutical dosage form according tothe present invention is adapted to be orally administered. Therefore,the dosage form or a part of the dosage form, in particular the shell,is shaped a swallowable manner. Preferably, this dosage form is formedas described above. Furthermore, this preferred embodiment may comprisea drug as the active pharmaceutical ingredient or active pharmaceuticalingredients that is, traditionally unsuitable for oral administration,in particular due to a small bioavailability, highly variable intra- orinter-individual plasma levels, degeneration or deactivation of the drugby digestive secretions and enzymes, dilution effects by intestinalfluids, poor resorbability, a high first pass effect and/or a very shortlength of stay at the absorption window. Among these drugs are, forexample: proteins and peptides such as insulin, buserelin, calcitonin ordesmopressin which is also called oesmopressin; hormones such asestrogen; as well as biotechnologically produced drugs such asantibodies, in particular rituximab.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention, in particular a dosage form for the applicationto a buccal, intestinal, rectal or vaginal mucous membrane, the sheetlike preparation provides, after its release by the release mechanism, arelatively large surface area. In particular, the sheet like preparationis adapted to come into contact with a relatively large surface area,preferably of the mucous membrane, preferably at the predetermined siteof release or site of action, after its release by the releasemechanism. Consequently and preferably, the sheet like preparation cancover a relatively large surface area of the mucous membrane, inparticular relatively large in comparison to the volume of thesheet-like preparation and/or to the amount of active pharmaceuticalingredients. Some particular advantages have already been describedabove. In particular, an enhanced resorption of the activepharmaceutical ingredient contained in the sheet like preparation can berealized. Moreover in a preferred variant of this embodiment, inparticular with a sheet like preparation with multiple layers, therelease of the active pharmaceutical ingredient can be directed into themucous membrane. Thus, the local concentration of the activepharmaceutical ingredient and/or the bioavailability and/or the rate ofabsorption and/or the local effect may be increased. Furthermore, theconcentration of the active pharmaceutical ingredient in the fluids thatare present near the mucous membrane may be decreased by a directedrelease, and therefore side effects may be reduced and/or thebioavailability and/or the local effect may be increased.

The term “relatively large” as used herein preferably refers to onething being a larger than another thing and/or one thing being largerthan such a thing or corresponding quantity would be in a traditionalembodiment of this thing, wherein preferably the extent, spatial extent,length, area, volume, surface area, cross-sectional area, envelopingcross-sectional area, contact area, covering area, diameter,circumference, path length, size, amount, quantity, scope, capacityand/or average size or scope is larger by a factor of preferably atleast 125%, preferably at least 200%, preferably at least 500%,preferably at least 1000%, and preferably at least 5000%. In particular,a relatively large surface area of a sheet like preparation according tothe present invention is larger than the surface area of a traditionaldosage form or its preparation. In particular, the surface area of asheet like preparation according to the present invention can berelatively large in comparison to the volume of the sheet likepreparation. In particular, an area, preferably surface area, can becompared with a corresponding volume. Preferably, an area is relativelylarger than a volume, if the square root of the area is larger than thecube root of the volume, preferably by a factor of at least 125%,preferably at least 200%, preferably at least 500%, preferably at least1000%, and preferably at least 5000%. Additionally or alternatively, arelatively large surface area of a sheet like preparation preferablyrefers to a surface area of the sheet like preparation that is largerthan the surface area of a traditional dosage form or its preparationwith the same amount of an active pharmaceutical ingredient, preferablyby the above given factors. It is to be understood, that the surfacearea of the sheet like preparation is an, at least essentially,uninterrupted surface area, while, in particular, a powder may alsocomprise a large surface area that is, however, not an essentiallyclosed surface, but rather a huge number of small surface areas of theindividual particles of the powder. In particular, mutatis mutandis,this also holds true for a drug or an active pharmaceutical ingredientthat is dissolved in a fluid. Especially, a contact with a relativelylarge surface area, in particular of a mucosa, means that the contactarea and/or the area that is covered, in particular by a sheet likepreparation, is larger than the area which would be in contact and/orcovered by a traditional dosage form or its preparation. Especially, ifthe traditional dosage form would dissolve in a fluid, then this fluidmay have a large contact area with their respective mucous membrane, butthe surface area would not be an essentially uninterrupted surface area,as described above, and/or the concentration of the drug or activepharmaceutical ingredient in said fluid may be lower than theconcentration in the sheet like preparation and/or or in the mucousmembrane covered by the sheet like preparation and/or in a fluid filledgap between the sheet like preparation and the covered area of therespective mucous membrane.

In a preferred embodiment the pharmaceutical dosage form according tothe present invention, in particular a dosage form for the applicationto a buccal, esophageal, nasopharyngeal, intestinal, rectal or vaginalmucous membrane, the release mechanism is adapted to release the sheetlike preparation while moving along the mucous membrane. It is to beunderstood, that the sheet-like preparation may be released onlypartially while moving along the mucous membrane. It is also to beunderstood, that the pharmaceutical dosage form or only a part of thepharmaceutical dosage form, in particular the release mechanism and/orthe sheet like preparation or a part of it, may move along the mucousmembrane. Additionally, the release may take place only during a part ofthe movement. In particular, the movement may take place along a path,preferably a predetermined movement path, and preferably the sheet likepreparation or a part of it is released along this path or a long a partof it. Furthermore, the movement may be an active movement or a passivemovement.

The term “active movement” as used herein preferably refers to amovement that is actively performed by the dosage form or a part of it,preferably by an actuator or movement mechanism of the dosage form.Thus, in particular, the pharmaceutical dosage form or a part of itgenerates a force to perform the movement.

The term “passive movement” as used herein preferably refers to amovement that is caused by external forces and/or movements. Inparticular, in a passive movement the dosage form or a part of it ismoved by external movements and/or forces. Preferably, such an externalmovement and/or force may be a gravitational force, a movement of amucous membrane, a movement of fluids that are present at apredetermined trigger site, application site or site of action, amovement of muscles, in particular of muscles that are near or belong toan organ with a respective mucous membrane, or forces generated by thosemovements. Preferably, the organ can be an esophagus, wherein themuscles of the esophagus perform a movement, in particular whenswallowing, and thus generate a force, preferably via the mucousmembrane of the esophagus and/or via a fluid, particularly a liquid suchas a beverage, water or saliva, wherein the force acts on the dosageform or a part of it when it is present within the esophagus or near toit, preferably in the oral region. Also preferably and/or alternatively,the organ can be a nose, a throat or a nasopharyngeal region, whereinair breathed through the nose or mouth moves the pharmaceutical dosageform or a part of it.

In particular, this advantageously allows the release of the sheet likepreparation along an extended, particularly elongated or oblong, regionof a mucous membrane. Preferably, the sheet like preparation can bereleased along a path of movement of the pharmaceutical dosage form or apart of it. This path is preferably predetermined by the structureand/or movement of the mucous membrane or organ and/or fluids containedin the lumen of said mucous membrane or organ. Therefore in a preferredvariant, the active pharmaceutical ingredient can be released along anextended, particularly elongated or oblong, region and/or along a pathof the mucous membrane. Consequently and preferably, a spatiallyextended region of the mucous membrane or the organ can be, inparticular locally, treated. Moreover in an alternate or further refinedpreferred variant, the sheet like preparation can release the activepharmaceutical ingredient locally to said extended region and/or over aprolonged time. Another advantage may arise from the fact, that, whenthe sheet like preparation is released during the movement, the sheetlike preparation can be aligned to the direction of the movement, inparticular along the path of the movement. Specifically with a dosageform, wherein the sheet like preparation comprises a first and a secondregion, those regions can be arranged at different sections of themucous membrane and/or the path of the movement. Besides that, inparticular by releasing the sheet like preparation during a passivemovement, the risk of injury may be reduced.

Specifically, an esophagus can be treated with an active pharmaceuticalingredient that is locally applied to its mucous membrane. So, inparticular, the active pharmaceutical ingredient can be applied to anextended region of the mucous membrane of the esophagus. Moreover, theactive pharmaceutical ingredient may act locally to the mucous membraneof the esophagus. Therefore, side effects due to systemic effect of theactive pharmaceutical ingredients may be reduced and/or the local effectto the mucous membrane of the esophagus, in particular due to thelocally increased concentration of the active pharmaceutical ingredient,may be enhanced. Moreover, when the sheet like preparation releases theactive pharmaceutical ingredient locally and/or over a prolonged time,the therapeutic response may be improved, and in particular the localeffect of the active pharmaceutical ingredient can be increased.Furthermore, in particular due to the spatially extended region ofaction, the necessity for a systemic administration may be reduced. Evenmore specifically, esophagitis, particularly eosinophilic esophagitis,can be treated by such a pharmaceutical dosage form. Here, a drug, inparticular the active pharmaceutical ingredient, may target the mucousmembrane of the esophagus and/or may preferably be selected from thegroup comprising: steroids such as corticosteroids, glucocorticoids,fluticasone, budesonide, clocortolone, perdesonide, hydrocortisone,clobetasonbutyrate, flumetason, flupredniden, hydrocortisone aceponate,hydrocortisone buteprate, hydrocortisone-17-butyrate,triamcinolonacetonid, amcinoid, betamethason-17,21-dipropionate,betamethason-17-valerate, desoximetasone, diflucortolon-21-valerate,fluocinolonacetonid, fluocinonid, fluticason-17-propionate,methylprednisolone aceponate, mometasonfuroat, pednicarbat orclobetasol-17-propionate; nitric oxide or nitric oxide forming agentssuch as isosorbide dinitrate or nitroglycerine, beclomethasonedipropionate, ciclesonide, pH buffers, antacids, calcium carbonate,magnesium carbonate or aluminum carbonate. Additionally oralternatively, the sheet like preparation particularly can comprise aninflammation regulator such as montelukast, interleukin receptors orinterleukin antibodies.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention, in particular a dosage form for the applicationto a buccal and/or esophageal mucosa and/or to a nasopharyngeal mucosa,the release mechanism comprises a string member, wherein the stringmember is expandable from a compact form to an expanded form. Inparticular upon activation of the release mechanism, the string membercan expand or can be expanded by another part of the release mechanismor by an external movement and/or force, preferably a movement of fluidsat a predetermined trigger site, a movement of a mucous membrane orgravitational force, to the expanded form. Preferably, the string membercomprises the sheet like preparation. The string member may comprise thesheet like preparation in the compact form and/or in the expanded form.Alternatively and preferably, the sheet like preparation may be adaptedto form the string member. Thus, the string member contains the activepharmaceutical ingredient. It is to be understood, that the stringmember may only partially comprise the sheet like preparation or thatthe sheet like preparation may only partially form the string member.Furthermore, only a part of the string member may convert from a compactform to an expanded form, while at least one other part of the stringmember remains in a compact form or an expanded form.

The term “compact form” as used herein preferably refers to a foldedform, coiled form, rolled form, coiled up form or collapsed form. Inparticular, a sheet like preparation has a smaller spatial extent and/orexposes a smaller amount of its surface in a compact form than in a formthat is not a compact form, particularly in an expanded form.Preferably, a sheet like preparation in a compact form is folded,collapsed, coiled, rolled, coiled up, compressed, lumped together orbrought into a smaller format in another way. In particular, a sheetlike preparation can have a predetermined size or spatial extent, whenit is in a compact form.

The term “expanded form” as used herein preferably refers to an unfoldedform, spread out form, opened up form, elongated form, stretched form oroblong form. In particular, a sheet like preparation has a greaterspatial extent and/or exposes a greater amount of its surface in anexpanded form than in a form that is not an expanded form, particularlyin a compact form. Preferably, a sheet like preparation in an expandedform is unfolded, spread out, opened up, unrolled, uncoiled, opened,elongated, stretched, expanded or brought into a bigger format inanother way. In particular, a sheet like preparation can have apredetermined size or spatial extent, when it is in an expanded form.Alternatively, the size or spatial extent of a sheet like preparationmay depend on the conditions present and a site of action or applicationsite, and thus may not be predetermined.

The string member advantageously allows releasing the activepharmaceutical ingredient, in particular to mucous membranes thatenclose a rather small lumen or cavity such as the esophagus or nasalcavity. Furthermore, the compact form of the string memberadvantageously makes it possible to provide a relatively smallpharmaceutical dosage form, in particular for oral administration, whichfacilitates swallowing the dosage form. Additionally, the string membermay expand, in particular unfold, uncoil, unroll, stretch or elongate,to the expanded form, and thus enable the release of the activepharmaceutical ingredient to an elongated region of a mucous membrane,in particular a buccal and/or esophageal mucosa and/or a nasopharyngealmucosa. In particular, it is beneficial that the exposed surface areaand/or the length of the string member or of the sheet like preparationexposed to the environment, in particular the mucous membrane, isincreased, when the string member expands, particularly elongates orstretches, from the compact form to the expanded form. By thisadvantageous way, the active pharmaceutical ingredient is protected inthe compact form and/or the release of the active pharmaceuticalingredient is enhanced by a rather large and/or long contact area in theexpanded form. An advantage of a preferred variant of this embodiment isthe use of the string member to support and/or to transport the sheetlike preparation, and thus particularly making it possible to choosedifferent substances and compositions for the sheet like preparation.Another advantage of an alternative and preferred variant results fromthe fact that the sheet like preparation forming the string member, andthus particularly making it possible to reduce the number of componentsof the dosage form and preferably to simplify the manufacturing of therelease mechanism and/or the sheet like preparation.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the sheet like preparation, in particular in anexpanded form, is string shaped, cord shaped, strip shaped or tubeshaped. Preferably or alternatively, the sheet like preparation isbendable.

In a further refined or alternate preferred embodiment of thepharmaceutical dosage form according to the present invention, the sheetlike preparation is adapted to form, in particular in an expanded form,a string, cord, strip or tube. Preferably, the sheet like preparation isbendable such that it can convert from a compact form, in particularwith a folded, collapsed, coiled, rolled or coiled up sheet likepreparation that may preferably have a string like, cord like, striplike or tube like shape, to the expanded form.

In particular, this advantageously allows the application of the dosageform and the release of the sheet like preparation to a mucous membranethat embraces a rather small lumen, in particular with a small diameter,and/or the treatment of a mucous membrane or an organ with a mucousmembrane that shows an adverse effect when larger regions of it arecovered or its lumen or a part of it is obturated by the sheet likepreparation. Specifically, such an adverse effect can be a gag reflex, asneeze stimulus or the blockage of fluid such as liquid, water,intestinal fluids or air. Another advantage is a possibly simplifiedmanufacture. Additionally and preferably, the spatial extent of theexpanded form, in particular the length of the sheet like preparation inits expanded form, in particular along its longitudinal and/orelongation axis, can be substantially larger than the spatial extent ofthe compact form, in particular the maximum diameter of the sheet likepreparation in its compact form. The term “substantially larger” as usedherein preferably refers to a ratio greater than or equal to 3:1,preferably 6:1, preferably 10:1, preferably 20:1, preferably 30:1, inparticular with respect to an aspect ratio, an area ratio or a volumeratio. It is to be understood that it may also be beneficial to limitthe maximum spatial extension and thus ratio to preferably 200:1,preferably 100:1, preferably 60:1, and preferably 40:1. In such amanner, in particular in a case where the volume of the sheet likepreparation stays constant, a minimum diameter along a cross-section,which is, at least essentially, orthogonal to the longitudinal axis ofthe sheet like preparation in its expanded form, can be ensured. On theother hand, in case of a sheet like preparation that is, at least in itsexpanded form, shaped as a tube with a relatively larger diameter,preferably with a diameter that corresponds to the diameter of therespective lumen enclosed by the respective mucous membrane, the mucousmembrane can be covered to a larger amount as compared to a sheet likepreparation with a smaller diameter, e.g. a string shaped sheet likepreparation.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the sheet like preparation, at least in theexpanded form, is longer than 5 cm, preferably longer than 10 cm,preferably longer than 30 cm, and preferably longer than 40 cm, andpreferably shorter than 95 cm, preferably shorter than 70 cm, andpreferably shorter than 50 cm. In this context it is to be understood,that a dosage form, and in particular a sheet like preparation, thatcomprises at least one end adapted to be held during swallowing requiresa length of the sheet like preparation that is correspondingly longercompared to the numbers given above, preferably by at least 5 cm,preferably by at least 10 cm, and preferably by at least 20 cm. Thus,such a sheet like preparation may preferably have length of, at leastessentially, 60 cm.

In this context and/or the present invention, the term “length” or termsrelating to length such as “longer” or “shorter” preferably refer to alength measured along the longitudinal and/or an expansion and/or anelongation axis of a respective object, in particular of the sheet likepreparation. Specifically, the length of a sheet like preparation in itsexpanded form, preferably elongated form, may be measured with a tapemeasure. More specifically, the sheet like preparation may comprise afirst end and a second end and the tape measure, in order to measure thelength of the sheet like preparation, may be guided along the sheet likepreparation from said first end to said second end. In particular, whenthe respective object, e.g. the sheet like preparation, follows, atleast essentially, a straight line, the length of the respective objectis the length along this line. Specifically, if this length is thelongest spatial extent, the direction of said straight line correspondsto the longitudinal axis.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the sheet like preparation has an area and/orsurface area between 0.5 and 25 cm², preferably between 2 to 25 cm²,preferably between 5 to 25 cm², preferably between 5 to 15 cm²,preferably larger than 0.5 cm², and preferably smaller than 40 cm².Preferably the ration of the length of the sheet like preparation andthe width of the sheet like preparation is between 40:1 and 400:1, orpreferably 60:1 and 300:1, or preferably 80:1 and 200:1. Said width canbe an average width of the sheet like preparation, measured, forexample, perpendicular to the length of the sheet like preparation. Saidratio can be a ratio of the length of the sheet like preparation and acircumference, in particular an average, of the sheet like preparation,wherein said circumference can be, for example, twice the width of asheet like preparation in the case of a strip-shaped sheet likepreparation.

In particular, this is beneficial for the application to a mucousmembrane. Specifically, the mucous membrane of an esophagus can becovered and/or locally treated by such a sheet like preparationcomprising the active pharmaceutical ingredient. It is to be understood,that depending on the specific embodiment of the dosage form that sheetlike preparation may, at least partially and preferably to asubstantially large extent, cover the mucous membrane of the esophagusand/or may extend, at least partially and preferably to a substantiallylarge length, along the longitudinal axis of the esophagus. Therefore ina preferred variant, the active pharmaceutical ingredient can bereleased on an extended region of the esophageal mucosa, and thus thisextended region can be treated. Moreover, in an alternate or refinedpreferred variant with a sheet like preparation that does not dissolveimmediately, but preferably dissolves in a time controlled manner and/oradheres to the mucous membrane, the active pharmaceutical ingredient canbe released over a prolonged time, and thus, in particular, thetherapeutic effect may be improved.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the release mechanism is an expansion mechanism,preferably elongation mechanism, adapted to expand the sheet likepreparation by leveraging an external movement, force or pressure.

It is to be understood, that the external movement, force or pressureparticularly can be present at a predetermined trigger site, applicationsite or site of action. Thus, it may serve as a key stimulus for thetrigger mechanism, too. Additionally or alternatively, the externalmovement, force or pressure may expand the sheet like preparation inconjunction with the release mechanism. In this context, an externalmovement, force or pressure refers to a movement, force or pressure thatis external to the pharmaceutical dosage form. Preferably, saidmovement, force or pressure is generated, at least partially, by thebody of a person or animal to whom the pharmaceutical dosage form isadministered, and thus is not external to said body. Therefore, such amovement can particularly be a passive movement. Preferably, such anexternal movement is a movement of a mucous membrane, a movement offluids that are present at a predetermined trigger site, applicationsite or site of action, a movement of muscles, in particular of musclesthat are near to or belong to an organ with a respective mucousmembrane, a peristaltic movement or a swallowing movement. Inparticular, the dosage form or a part of it may, preferably passively,move relative to the body of a user, in particular to a mucous membraneor organ. Preferably, such an external force can be caused by saidexternal movements or is a force generated by a fluid surrounding thedosage form, a force generated by a mucous membrane, which is inparticular in contact with the pharmaceutical dosage form or a part ofit, a force generated by muscles that are near to all belong to an organwith a respective mucous membrane. Preferably and in a similar manner,such an external pressure can be caused by said external movements orcan be a pressure of a fluid surrounding the pharmaceutical dosage form,in particular generated by a respective mucous membrane or correspondingmuscles, or a pressure directly applied to the dosage form or a part ofit, in particular by a respective mucous membrane or correspondingmuscles, in particular by a gastrointestinal wall. It is to beunderstood, that additionally a gravitational force may act on thedosage form and parts of it, and therefore may improve, increase,decrease, hamper or facilitate said external movement, force orpressure. Specifically, a buoyancy force may be regarded as an externalforce and/or utilized for the expansion of the sheet like preparation.

Specifically, in case of an orally administered dosage form preferablyfor the application to the esophagus, the external movement may be themovement of the dosage form while it is swallowed. Therefore, themuscles of the esophagus generate a force that acts on the dosage formor a part of it. In particular, the mucous membrane of the esophagus canact directly on the dosage form and/or can act indirectly to the dosageform, preferably via a fluid, particularly a liquid such as a beverage,water or saliva, which is preferably swallowed together with the dosageform. Out of those movements forces or pressures may arise. From anotherpoint of view, forces and/or pressures of the esophagus, its mucousmembrane and muscles may cause said movements. In particular, the changeof pressure of a swallowed fluid can be used as a key stimulus for thetrigger mechanism. Therefore, the expansion of the sheet likepreparation may be improved and/or the release mechanism may besimplified. Preferably, the release mechanism can essentially passivelyrelease the sheet like preparation; so, the expansion of the sheet-likepreparation takes place without generating an additional force by thepharmaceutical dosage form. Thus, an active release mechanism comprisingan energy storage, e.g. a gas forming agent or a spring, is not requiredor, at least, the energetic requirements for a release mechanism, whichonly partially facilitates the passive expansion, reduced. Furthermore,this preferred embodiment, in particular, allows a release of the sheetlike preparation during the swallowing of the dosage form. Finally, thecosts for manufacturing may be reduced, the safety may be increased, theuser convenience may be enhanced and/or the reliability may beincreased.

An advantage of a preferred embodiment that leverages an externalmovement, force or pressure and the pharmaceutical dosage form can beparticularly a reduced risk of injury, and increased safety, an improveduser convenience and/or a reduced manufacturing cost. Preferably, therisk of injury can be reduced because the required movement, force orpressure to expand the sheet like preparation is external, and thus notgenerated by the dosage form, but rather, in particular, by the body ofa user itself. Additionally or alternatively, also the manufacturing maybe simplified because the release mechanism, preferably expansionmechanism, does not have to generate the required force, movement orpressure by itself but rather utilizes the external movement force orpressure, and thus corresponding additional structures and/or parts canbe spared.

Additionally or alternatively, the leveraging of an external movement,force or pressure to expand the sheet like preparation may beadvantageously combined with the release of the sheet like preparationwhile moving along the mucous membrane. In particular, this combinationcan release the sheet like preparation, at least partially, along itspath of movement and this release is facilitated or is completelyperformed by utilizing just exactly this movement. Therefore, themanufacture may be simplified, the costs may be reduced, the safety maybe increased, the user convenience may be enhanced and/or thereliability may be increased.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the release mechanism and/or the trigger mechanismis formed, at least partially, by the sheet like preparation. This mayadvantageously allow a simplified construction and/or manufacture. Inparticular, the manufacturing costs can be reduced. Preferably, thereliability of the pharmaceutical dosage form can be enhanced,particularly due to a reduced number of parts.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the pharmaceutical dosage form in particular theshell, contains the sheet like preparation in a compact form, preferablya folded, collapsed, coiled, rolled or coiled up form, and the releaseof the sheet-like preparation by the release mechanism, in particularexpansion mechanism, preferably elongation mechanism, results in anexpansion, preferably an unfolding, unwinding, stretching or elongation,of the sheet like preparation, in particular to an expanded form. Thisespecially provides for the advantages described above regarding thecompact and/or the expanded form. In particular, an elongation along anaxis or movement path, preferably along the longitudinal axis of thesheet-like preparation in its expanded form, advantageously allows therelease of the active pharmaceutical ingredient over an oblong region ofa mucous membrane as well as a small dosage form compared to said oblongregion, and thus preferably an orally administrable dosage form.

In a preferred embodiment of the dosage form according to the presentinvention the trigger mechanism is a holding device that is a part of oris attached to the sheet like preparation. In particular, this isbeneficial to keep, at least a part, preferably an end, of the sheetlike preparation and/or string member in a fixed position, while otherparts of the sheet like preparation or of the dosage form move.Preferably, the holding device is adapted to be fixed, in particular theattached, positioned or mounted, to a predetermined region or part of abody of the user or a predetermined position. Furthermore, a forceacting on the holding device may serve as a key stimulus. Especially, anexternal movement, force or pressure that acts on the pharmaceuticaldosage form may cause such a force acting on the holding device. It isto be understood, that the holding device may also be attached to thesheet like preparation in an indirect way. In particular, the sheet-likepreparation may transmit a force to the holding device, and vice versa,by another part of the pharmaceutical dosage form. Especially it is tobe understood, that the string member or a part of it may form theholding device.

In a preferred embodiment of the dosage form according to the presentinvention, in particular a dosage form for the oral administration, thetrigger mechanism, in particular the holding device, is adapted to befixed in an oral cavity, preferably to a tooth, to a tongue, a lip or toan oral mucous membrane. Additionally or alternatively, the triggermechanism is adapted to be held in a hand, preferably of a user, duringswallowing of the pharmaceutical dosage form.

In particular, this advantageously allows ensuring a desired position ofthe trigger mechanism, preferably holding device, especially during theadministration, e.g. swallowing, of the pharmaceutical dosage form.Preferably, in this manner, a position of the trigger mechanism, inparticular holding device, can be predetermined for the application.Preferably and alternatively, the position of the trigger mechanism canresult out of a random attaching, in particular, to a region of therespective mucous membrane. Specifically, the trigger mechanism,preferably holding device, can have adhesive properties and then, beforeswallowing of the pharmaceutical dosage form, randomly attach to aregion of a buccal mucous membrane or a tongue. This is particularlyadvantageous, because a user may simply put the pharmaceutical dosageform into the mouth and then, preferably with a liquid, swallow it,wherein the trigger mechanism, preferably holding device, is attached inthe oral cavity without further and/or specific action of the user.

The term “holding device” as used herein preferably refers to a devicethat is adapted to hold itself, and possibly further parts that areconnected to it, e.g. a part of a sheet like preparation, at a definedposition. In particular, a holding device is a handle, sling or adhesivetape or comprises an adhesive region. Moreover, the holding device maybe adapted to build up and maintain a connection that can transfer aforce between the holding device and a region where it is attached.Furthermore, this connection may be built up or maintained, while thedosage form and/or the sheet like preparation is in its compact formand/or its expanded form. Preferably, the holding device may holditself, and possibly further parts, at a defined position or region by aforce fit, in particular in a frictionally engaged manner,form-fittingly or by material engagement, in particular by mucoadhesion,preferably by an adhesive bond.

An advantage of such a holding device may arise from the fact, that aforce acting on and/or a movement of the pharmaceutical dosage form canbe used as a key stimulus for the trigger mechanism, wherein preferablythe holding device is or is a part of the trigger mechanism, to triggerthe release of the sheet like preparation. Preferably, an embodimentaccording to the invention with a holding device can be advantageouslycombined with utilizing external movement, pressure or force to expandthe sheet like preparation. In particular, an external movement and/orforce can serve as a key stimulus for the trigger mechanism, wherein thetrigger mechanism preferably triggers the release of the sheet likepreparation by the release mechanism, and then said external movement,force or an external pressure is utilized to expand the sheet likepreparation, preferably by the release mechanism. Particularly this isthe case, when the dosage form according to the present inventionpassively moves relative to the position where the holding device isfixed. Also preferably, embodiments with a holding device and/orleveraging an external movement, force or pressure can be advantageouslycombined with the release of the sheet like preparation during amovement of the dosage form or a part of it along the mucous membrane.In this case, a controlled and/or targeted triggering of the release maybe achieved, a release and/or contact of the sheet-like preparation atthe desired region of the mucous membrane may be ensured and/or due toutilizing the external movement, force or pressure the release mechanismmay be simplified, manufacturing costs may be reduced, user conveniencemay be enhanced and/or the safety may be increased.

In certain embodiments fixing the holding device in the oral cavity canincrease the user convenience. Furthermore, a holding device that isadapted to be fixed in the oral cavity may be manufactured in a simple,and thus cost efficient way, and/or may be particularly reliable,especially because the user may notice whether the holding device isproperly fixed before continuing with the administering of the dosageform, e.g. swallowing the dosage form or a part of it. Similaradvantages may arise for a holding device adapted to be held in a handwhile administering of the dosage form.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention, at least during the release of the sheet likepreparation, the released portion of the sheet like preparation and thepharmaceutical dosage form move relatively to each other and therebydefine a movement path of the dosage form. Additionally, when viewing inthe direction of the movement path, the enveloping cross-sectional areaof the dosage form is larger than the enveloping cross-sectional area ofthe sheet like preparation. In particular, the envelopingcross-sectional area of the dosage form can refer to the envelopingcross-sectional area of a swallowable part of the dosage form,preferably the shell. In particular, the enveloping cross-sectional areaof the sheet like preparation can refer to the envelopingcross-sectional area of the released part of the sheet like preparation.It is to be understood, that these relations particularly hold trueduring the release of the sheet like preparation. In particular, thesheet like preparation may expand, and thus have a larger envelopingcross-sectional area than the dosage form afterwards. It is to beunderstood, that the above described relations are particularlyimportant for the portion of the sheet like preparation that just hasbeen released by the dosage form. Preferably, the length of thisportion, measured along the movement path, is, at least essentially, aslong as the length of the dosage form, measured along the movement path,preferably twice as long, preferably five times as long, and preferablytwenty times as long. Particularly, the relation of envelopingcross-sectional areas can be reflected and/or correspond to the relationof the respective maximum diameters or minimum diameters, which followthe respective transverse axis or are, at least essentially, orthogonalto the respective longitudinal axis or direction of the movement.

This may advantageously allow facilitating the movement of the dosageform by swallowing it or by peristaltic movements. Certain variants ofthis embodiment can improve the user convenience and/or reduce the riskof injury. In particular, as at least a section of the released sheetlike preparation that is next to the dosage form has a smallercross-sectional area, such a dosage form is better a swallowable.Specifically, this tapering behind the dosage form helps the muscles ofthe esophagus to swallow the dosage form. Preferably, the dosage form,in particular the shell such as a capsule, also tapers at least inand/or against the direction of the intended movement path, and thusfurther facilitates swallowing it. Furthermore, the dosage form may beadapted such that its longitudinal axis is, at least essentially,parallel to the intended to movement path. Moreover, the dosage form mayrelease the sheet like preparation against the direction of the intendedmovement path, e.g. at the rear side of the dosage form regarding to theintended movement path or movement of the dosage form.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the sheet like preparation has at least a firstportion and a second portion with different enveloping cross-sectionalareas, in particular when viewed in the direction of the movement path,wherein the portion that is released before the other portion has asmaller cross-sectional area. In an alternate and preferred embodimentthe sheet like preparation tapers from a second end of the sheet likepreparation to the first end of the sheet like preparation, wherein thefirst end of the sheet like preparation is on the side of the sheet likepreparation that is released first. In particular, for the applicationto the esophagus both embodiments result in a sheet like preparationthat is, after its release, smaller in the upper region of the esophagusand the oral cavity and larger in the lower region of the esophagus.This may beneficially facilitate the swallowing the dosage form and/orincrease the user convenience, in particular suppress or avoid a gagreflex. In a preferred variant the first portion is a string member.

It is to be understood, that the terms “pharmaceutical dosage form” and“dosage form” as used herein are preferably interchangeable. Preferably,a dosage form can have non-pharmaceutical applications. In particular, adosage form can be used for the therapy and/or for the diagnosis of adisease.

It is to be understood, that certain embodiments of a pharmaceuticaldosage form according to the present invention differ from a catheter inthat they are, at least essentially, fully enclosed by the body of auser after the administration. Additionally or alternatively, theadministration is performed without additional tools and/or withoutapplying a force or movement that is external to the body of a user.Preferably, a pharmaceutical dosage form according to the presentinvention can be administered by the user without professional help.This is particularly beneficial, if the dosage form is to beadministered on a regular, in particular daily, basis. Furthermore, theuser convenience may be improved, the safety may be increased and/or therisk of injury may be reduced. Especially, the convenient administrationis also beneficial for the treatment of animals. Similarly it is to beunderstood, that a pharmaceutical dosage form according to the presentinvention is different from a stent. In particular, a stent doesgenerally not comprise a trigger mechanism in the sense of the presentinvention. Moreover, the object of a stent generality is to keep open ahollow organ. Certain embodiments of a pharmaceutical dosage formaccording to the present invention may also keep open a hollow organ,however besides the object of keeping open a hollow organ their objectis at least to improve the local application of a drug, particularly anactive pharmaceutical ingredient. Some of the other embodiments of apharmaceutical dosage form according to the present invention have theobject to improve the local application of a drug, in particular anactive pharmaceutical ingredient, and to let a hollow organ close, inparticular even during the application of the dosage form. Particularly,this may be a achieved by a pharmaceutical dosage form comprising astring member or a sheet like preparation that is, in particular in anexpanded form, string shaped, cord shaped, strip shaped or tube shaped.In particular, this is especially advantageous for the treatment of theesophagus.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the pharmaceutical dosage form, in particular theshell, comprises at least one aperture, and is adapted to release thesheet like preparation by passing it through the at least one aperture.A preferred variant of this embodiment advantageously protects the sheetlike preparation by containing it in the shell. Furthermore, thereliability of a dosage form releasing the sheet like preparationthrough the aperture may be increased. Additionally or alternatively,the administration may be improved; in particular the user conveniencemay be enhanced, because the aperture may advantageously allow thecontrolled and/or directed release of the sheet like preparation.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention comprising at least one aperture the triggermechanism and the sheet like preparation are, at least partially, onopposed sides of the at least one aperture. Preferably, the triggermechanism is not or only partially contained in the shell of the dosageform. Preferably, the sheet like preparation is, at least partially,contained in the shell of the dosage form. This may improve thereliability and/or user convenience of the pharmaceutical dosage form.In particular, the storability can be improved. Besides that, this mayadvantageously allow to trigger the trigger mechanism with a keystimulus that is external to the dosage form and does not have to betransferred into an inner part of the dosage form, in particular into ashell of the dosage form. Moreover, the trigger mechanism may be exposedto the outside and thus be more sensitive to a possible key stimulus.Preferably, the trigger mechanism can comprise or is a holding device,which may be exposed to the outside and/or fixed in the oral cavity orheld in a hand.

In a preferred embodiment of the pharmaceutical dosage form according tothe present invention the release mechanism comprises or is an unwindingdevice that is adapted to release the sheet like preparation byunwinding it. This may advantageously allow releasing a sheet likepreparation that is rolled, coiled or winded in its compact form.Furthermore, such an unwinding device may be conveniently formed by thesheet like preparation or a part of it, preferably by forming a coil.Preferably, such a coil may be supported with a rod, which may improvethe ability to unwind it.

In certain embodiments of the pharmaceutical dosage form according tothe present invention the sheet like preparation is in a solid-state, inparticular while it is in its compact form and/or immediately after itsrelease. This may beneficially enhance, enable or facilitate some of theabove mentioned advantages. In particular, this may enhance thestorability, when it is in a solid state prior the release. Inparticular, this may enhance and/or enable a targeted and/or sustainedrelease of the active pharmaceutical ingredient, when it is in a solidstate after its release. Additionally or alternatively, in certainembodiments of the pharmaceutical dosage form according to the presentinvention the sheet like preparation is adapted to dissolve, e.g.bio-degenerate, immediately, after a delay, in a time controlled manneror upon a stimulus after its release. This may beneficially enhance,enable or facilitate some of the above mentioned advantages. Inparticular, this can improve the user convenience, because the sheetlike preparation does not need to be removed.

All embodiments of the pharmaceutical dosage form according to thepresent invention show the advantage that a pharmaceutical dosage formis provided in which the bioavailability of the active pharmaceuticalingredients contained in the administered dosage form is improved or inwhich, in particular additionally or alternatively, the local effect ofthe active pharmaceutical ingredient is improved. Additionally, by meansof a pharmaceutical dosage form according to the present invention adosage form is provided in which the release of the activepharmaceutical ingredient at its predetermined site of action isimproved. Further advantageous of the pharmaceutical dosage formaccording to the present invention are:

-   -   Equal effect possible at lower dosages    -   Reduction of side effects due to a low dosage    -   Faster onset of effect by direct contact with the application        site.

Exemplary embodiments of the present invention will be described ingreater detail below with reference to the accompanying drawings andsamples, from which further features, advantages, and embodiments can belearned.

FIG. 1 shows a schematic perspective illustration of a pharmaceuticaldosage form according to the invention in accordance with a firstembodiment of the invention in an initial state;

FIG. 2 shows a schematic perspective illustration of a pharmaceuticaldosage form according to the invention in accordance with the firstembodiment of the invention in a state after the release of thesheet-like preparation by the release mechanism;

FIG. 3 shows a schematic perspective illustration of a pharmaceuticaldosage form according to the invention in accordance with a secondembodiment of the invention in an initial state;

FIG. 4 shows a schematic perspective illustration of a pharmaceuticaldosage form according to the invention in accordance with the secondembodiment of the invention in a state after the release of thesheet-like preparation by the release mechanism;

FIG. 5a, 5b show a schematic perspective illustration of apharmaceutical dosage form according to the invention in accordance witha third embodiment of the invention in an initial state;

FIG. 5c shows a photograph of a pharmaceutical dosage form according tothe invention in accordance with the third embodiment of the inventionin an initial state;

FIG. 6a, 6b show a schematic perspective illustration of apharmaceutical dosage form according to the invention in accordance witha fourth embodiment of the invention in an initial state;

FIG. 6c shows a photograph of a pharmaceutical dosage form according tothe invention in accordance with the fourth embodiment of the inventionin an initial state;

FIG. 7 shows the schematic structure of an example of a three-layeredfilm-shaped preparation of the present invention;

FIG. 8a, 8b show a schematic illustration of a pharmaceutical dosageform according to the invention in accordance with a fourth embodimentof the invention; and

FIG. 8c illustrates the enveloping cross-sectional areas of the fourthembodiment of the invention.

In FIG. 1 a schematic perspective illustration of the pharmaceuticaldosage form 1 according to the invention in accordance with a firstembodiment of the invention in an initial state is shown. FIG. 2 showsthe pharmaceutical dosage form 1 from FIG. 1 in a state after therelease of the sheet-like preparation 3 by the release mechanism 4. InFIGS. 1 and 2 it can be seen that the illustrated pharmaceutical dosageform 1 comprises, in particular for the oral administration, acapsule-shaped shell 2, the shell contains a sheet-like, in particularfilm-shaped, foil-shaped or wafer-shaped preparation 3 comprising theactive pharmaceutical ingredient in form of a folded, respectivelyunfoldable wafer 3, as well as a release mechanism 4 and a triggermechanism 5 that is adapted to trigger the release of the sheet-likepreparation 3 by the release mechanism 4 at a predetermined site ofaction, in particular of the gastrointestinal tract. The shell 2comprises an aperture 6 a on the one side an aperture 6 b on theopposite side of the dosage form 1, in particular the aperture 6 b isformed as a slit. The aperture 6 a is covered by a trigger mechanism 5.When this aperture, at the site of action, is contacted with fluidsurrounding the dosage form there, it dissolved and fluid can come intocontact with the inner space 7 of the shell 2. The aperture 6 a is atleast partially covered by the trigger mechanism 5, e.g. a solublepolymer, which is adapted to trigger the release of the sheet-likepreparation 3 by the release mechanism 4 after contacting thepharmaceutical dosage form 1, in particular the trigger mechanism 5,with a key stimulus. Here, a predetermined change of a physical orchemical parameter or a fluid surrounding the dosage form 1, inparticular gastric juice in the stomach, or alternatively also fluid ofthe small intestine, which has a substantially lower pH value comparedto the oral cavity and pharyngeal cavity, serves as a key stimulus totrigger the trigger mechanism 5. The trigger mechanism 5 is made of asubstance whose solubility and/or solidity depends on the pH value thatis present in the stomach.

In FIG. 2 the trigger mechanism 5 is not shown any more because it hasalready dissolved. The shell 2 is made of a material that is essentiallyinsoluble in the gastric juice, e.g. hard gelatin or starch that isadditionally coated with other polymers in order to remain stable in thegastric juice, which are stable on their own (e.g. Eudragit etc.). Therelease mechanism 4 is embodied as an expansion mechanism 4 thatcomprises a wick system, more specifically the gas driven expansionsystem, to which fluid is directed through the wick system by capillaryforces. An expansion of the expansion mechanism 4 can result in anopening of the shell 2 at the predetermined breaking point 8 or isalternatively suitable to rupture a coating sealing the aperture 6 b.This coating protects the dosage form 1 from an unwanted entry of fluidthrough the aperture 6 b in an initial state. The latter can be seen inthe interplay between FIG. 1 and FIG. 2. Preparation 3 is contained inthe shell 2 in a folded form that is shown in FIG. 1, wherein—as shownin FIG. 2—the expansion of the expansion mechanism 4 results in anunfolding of the preparation 3, wherein the preparation 3 escapesthrough the slit 6 b and inflates like a balloon. For this purpose, agas-forming agent, e.g. a powder that optionally can be incorporatedinto a wick system, in particular comprising capillaries e.g. fibers,that can absorb a fluid, is arranged in the area of the shell 2, that isshown in FIGS. 1 and 2 on the left hand side, as a release mechanism 4and expansion mechanism 4. For example, sodium hydrogen carbonate orcitric acid or alternatively a pressurized gas is suitable as agas-forming agent, here.

In particular, a release mechanism and the expansion mechanism is formedin such a way that the formed gas is directed only into the waferrespectively balloon 3 and cannot escape at another place. At the timeof release, the powdery gas-forming agent and the wick system 4 are keptin contact. Therefore it is beneficial when the gas-forming agent isincorporated into the wick system.

In case of a liquid or partial liquid gas-forming agent, a separatedcompartment may contain the gas-forming agent, that compartment is atleast partially formed out of the outer shell 2 of the dosage form.Thus, the gas-forming agent is arranged in a part of the shell 2 that isopposed to the part of the shell by containing the preparation3—arranged at the right hand side of the shell in the figures. Thegas-tight shell 2 which can be filled with a gas comprises a centralaperture 6 a that is circumferentially attached at an inner edge of theshell 2. After triggering of the release mechanism, liquid is directedto the release mechanism in form of a gas-forming agent through the wicksystem 4 and gas is formed by the gas-forming agent and is directed intoan inner space of the sheet-like preparation 3. For this purpose, thispreparation is formed as a gas-tight shell that can be filled with agas, in particular a balloon, as in particular shown in FIG. 2.

In FIG. 1 the preparation 3 formed as a gas-tight gas-fillable shell ispresent in folded form. Furthermore, it can be seen from FIG. 1 that theshell is divided at its periphery. It is also seen from FIG. 1, that theshell comprises at least one predetermined breaking point. It is to beunderstood that, depending on the actual embodiment, it can besufficient that the balloon 3 protrudes through the slit 6 b only.However, further experiments have shown that in order to completelyunfold the balloon a predetermined breaking point 8 at the shell 2 maycompletely rupture or fold open, in particular by the gas pressuredeveloped in the balloon 3. In particular, such a mechanism can be heldtogether by a coating of the slit 6 b in the initial state. Such acoating may also be chosen such that it—in particular when it is chosenfrom a similar or from the same material as the trigger mechanism 5,this coating is etched or dissolved at the trigger site, respectivelysite of action, such that gas pressure can open up the capsule 2. Forthis purpose, it may be beneficial, that the coating of the slit 6 bdissolves more slowly than the trigger mechanism 5. It is to beunderstood that just one predetermined breaking point 8 or a foldingmechanism at this position may be provided or just a slit 6 b or acombination thereof may be provided in different actual furtherembodiments. The actual embodiment may be chosen by a person skilled inthe art depending on the size and scope of application and depending onthe actually used materials.

Gastric juice or intestinal fluid enters at the predetermined triggersite, here e.g. in a stomach or in the intestine, the inner space 7 ofthe shell through the aperture 6 a and results in a formation of gas bythe gas-forming agent. Along with this gas is directed into the innerspace of the wafer 3 which inflates like a balloon at the site ofapplication and expands. Along with this the capsule-shaped shell 2 isopened at one of its—here right end—by e.g. the breaking of thepredetermined breaking point 8 by the pressure of the expanding balloon3 and/or by protruding of the balloon 3 through the aperture 6 b. Inthis way, a complete unfolding and release of the wafer 3 of the capsule2 is possible. In particular, such a construction allows forming arelatively large wafer surface which can rest over a relatively largearea of the gastric wall in order to release the active pharmaceuticalingredient. Alternatively and in particular, such a construction allowsforming a relatively large wafer surface which can rest over arelatively large area of the intestinal wall in order to release theactive pharmaceutical ingredient. It is also to be understood that apart of the wick system 4 may stick out of the shell and direct thefluid into the inner space of the shell 2. The portion of the wicksystem 4, which is located outside the shell, is expediently covered bythe release mechanism 5 in an initial state, and released uponactivation.

FIG. 3 shows a schematic perspective illustration of a pharmaceuticaldosage form 1 according to the invention in accordance with a secondembodiment of the invention in initial state. Again, the pharmaceuticaldosage form 1, which is, in particular, suitable for oral application,comprises a shell 2 wherein the shell 2 contains a sheet-like, inparticular film-shaped, foil-shaped, or wafer-shaped preparation 3comprising the active pharmaceutical ingredient in form of a foldedwafer 3 as well as a release mechanism 4 and a trigger mechanism 5 thatis adapted to trigger the release of the wafer 3 by the releasemechanism 4 at a predetermined site of action, e.g. the gut. The shell 2comprises a central aperture 6 a, respectively 6 b, at both sides thatare closed by a coating, e.g. a dissolvable coating or somethingsimilar. After the application, the apertures 6 a and 6 b are covered,whereby the trigger mechanism 5 can come into contact with a fluid.However, an aperture does not have to be present, because the triggermechanism may also be located at the circumference of the dosage form 1.The fluid of the gastrointestinal tract or the small intestinesurrounding the shell 2 comes into contact with the inner space 7 of theshell after dissolution of the coating. The trigger mechanism 5 isadapted to trigger the release of the sheet-like preparation 3 by therelease mechanism after contacting the pharmaceutical dosage form, inparticular of the trigger mechanism 5, with a key stimulus. For example,in the illustrated embodiment, an action of pressure caused by anintestinal peristalsis or a specific pH value usually prevailing oroccurring at the site of action serves as a key stimulus. In theillustrated embodiment, the trigger mechanism is formed by a solublepolymer that is located at the inside of the tube elements 11 and 12. Inparticular, an action of pressure can serve as a key influence if thelevers of the capsule are held together with a material that breaks uponaction of pressure. The release mechanism 4 is constructed as anexpansion mechanism 4, specifically as a mechanical expansion system,wherein an expansion of the expansion mechanism 4 results in anunfolding of the wafer 3.

FIG. 4 shows the embodiment illustrated in FIG. 3 in an unfolded state.The shown embodiment comprises, as part of the mechanical expansionsystem, a plurality of joint or lever elements 13, which are arranged atboth free ends of the shell 2 in the area of the central aperture 6, aswell as a spring element 10 that is arranged within the tube elements 11and 12 that are slit into each other. In particular, the joint or leverelements 13 a of the first tube 11 and the joint or lever elements 13 bin in tube 12 are arranged alternately in a closed initial state of thedosage form 1 as shown in FIG. 3 such that in the closed state as shownin FIG. 3 the joint or lever elements 13 a of the first tube 11 and thejoint or lever elements 13 b of the second tube form a shell 2,respectively a cladding, that is flipped open upon release and thatopens up the preparation 3.

In particular, the length of the lever of the joint or lever elements 13a of the first tube 11 and of the joint or lever elements 13 b of thesecond tube 12 have the whole length of the folded dosage form 1 in thisarrangement. It is to be understood that in the case, in which the leveror joint elements 13 a and 13 b are arranged opposing each other, themaximum length of the lever is limited to half of the length of thedosage form 1. In this case, the first and the second tube element 11and 12 as well as the lever and joint elements 13 a and 13 b arearranged such that the lever and/or joint elements 13 a, respectively 13b, form a wreath structure and the lever and joint elements 13 a at thetube element 11 and the lever and joint elements 13 b at the tubeelement 12 are respectively attached in a slit at the tube element 11,respectively 12, when the dosage form 1 is viewed from the rear or fromthe front, thus looking on the smallest surface area of a dosage form 1.The resilient force of the spring 10 pushes the lever and joint elements13 a and 13 b through this slit 16 to the outside, and the wafer 3 isunfolded as the cladding or shell parts 17 that are pivotally attachedat the lever and joint elements 13 a and 13 b, respectively, swingoutwards. In this context it is to be understood that the pivotallyattached cladding or shell parts 17 may also form lever or jointelements and may be understood as such.

In such an arrangement, it is beneficial if, as shown in FIG. 3, in aclosed state of the dosage form 1 the cladding or shell parts 17 of thefirst tube 11 forming joint or lever elements and the cladding or shellparts 17 of a second tube 12 forming joint or lever elements arearranged alternately such that preferably in a closed state, thecladding or shell parts 17 of a first tube11 forming joint or leverelements and the cladding or shell parts 17 of the second tube 12forming joint or lever elements form the shell and/or the cladding 2.The wreath structure at a first end of the dosage form 1, in particularat an end of the first tube element 11, and the wreath structure at asecond end of the dosage form 1, in particular at an end of the secondtube element 12, are offset in a rotationally symmetric manner. A jointor lever movement of the joint elements 13 a and 13 b cause an unfoldingof a sheet-like preparation 3, that is folded in an initial state in thedosage form 1, by the spring force driven movement in the slit 16 to theoutside as the cladding or shell parts 17 swing outwards such that thesheet-like preparation 3 unfolds at a predetermined site of action in aparticular advantageous manner, and preferably can contact a mucousmembrane or the intestinal wall.

The shell 2 comprises the tube elements 11 and 12 that are pushed intoeach other by a spring 16 arranged in the tube elements 11 and 12 insuch a way that they can move relatively to each other and that arecentrally arranged in the main longitudinal axis of the dosage form 1.By the action of pressure of the intestinal peristalsis or thedissolution of a coating and the subsequent entry of fluid to triggerthe release mechanism the mechanical expansion system is triggered andby means of the spring driven joint or lever elements 13 a, 13 b incombination with the shell or cladding elements 17 the unfolding of thewafer 3 and thus its release out of the shell is effectuated. Inparticular, this expansion thus can be assisted or directed by providingat least a further joint or lever element.

FIG. 5a, 5b show a schematic perspective illustration of apharmaceutical dosage form 1 according to the invention in accordancewith a third embodiment of the invention in an initial state and FIG. 5cshows a photograph of the pharmaceutical dosage form according to theinvention in accordance with a third embodiment of the invention in aninitial state. FIG. 5a shows the embodiment in a side view and FIG. 5bshows a view to the tip of the embodiment. This pharmaceutical dosageform 1 according to the invention is adapted for the application onto amucous membrane, in particular onto a vaginal mucous membrane, but alsoonto a rectal mucous membrane, and comprises the sheet-like, inparticular film-shaped, foil-shaped or wafer-shaped preparation 3 thatcomprises the active pharmaceutical ingredient in form of a wafer 3which is circumferentially arranged at a longitudinal section of thecylindrical main body of the dosage form 1 that tapers on one side. Inparticular, the main body may be a tampon that is essentially formed outof a swellable material. This swellable material may form both, therelease mechanism 4 and the trigger mechanism 5, which swells uponcontact of the dosage form 1 with a fluid, in particular a vaginalfluid, and thus unfolds the preparation 3. Because of the increase ofthe diameter of the dosage form 1 due to the swelling, also thecircumference of the preparation 3 increases. This is the case becausethe preparation 3 may be folded into grooves or depressions of the mainbody of the dosage form.

FIGS. 6a, 6b, and 6c show an alternative embodiment that defer from theembodiment shown in the FIGS. 5a, 5b, 5c in that here the preparation 3is partially folded outwards. Due to swelling of the main body of thedosage form at a predetermined site of action, here, in particular, therectum or preferably the vagina, the release of the sheet-likepreparation 3 by the release mechanism 4 is triggered.

It is to be understood that the main body of the dosage form 1 maycomprise grooves or may not comprise grooves depending on theembodiment.

In particular, however, a polymer being a glue can serve as a furthertrigger mechanism 5, wherein the polymer dissolves at least partially orcompletely upon contact with the fluid at the trigger site. Inparticular, such a polymer may attach the preparation 3 to the main bodyor may, additionally or alternatively, glue the foldings of the wafer 3together. In particular, this may result in that the wafer 3 does notunfold as the polymer acting as a trigger mechanism 5 is not or is atleast partially not dissolved. In the context of the embodiments shownin FIG. 5 and FIG. 6, it is also to be understood that these areparticularly suited for embodiments in which a rapid and immediaterelease and dissolution and thus a relatively fast and immediatecontacting of the wafer with the site of application, in particular ofthe vaginal mucous membrane, is intended.

FIG. 7 shows the schematic structure of a three-layered sheet-likepreparation. A sheet-like preparation, like it is contained in thepharmaceutical dosage form 1 according to the invention, may have athickness of 0.01 mm to 2 mm, preferably 0.03 mm to 1 mm, preferably0.05 mm to 0.1 mm, wherein the sheet-like preparation 3 has an areabetween 0.5 and 20 cm², preferably between 1 and 10 cm². In particular,a sheet-like preparation 3 comprises at least one layer comprising anactive pharmaceutical ingredient. The sheet-like, in particularfilm-shaped, foil-shaped or wafer-shaped preparation 3, which preferablyhas the shape of a wafer 3, contains an active pharmaceutical ingredientwith an active ingredient content of 0.5 to 40% by weight, preferably 1to 30% by weight, and more preferred 5 to 20% by weight. A sheet-likepreparation 3 may have a single-layered or a multi-layered structure outof one or more layers 9, wherein at least one first layer 9 a containsan active pharmaceutical ingredient. FIG. 7 shows the exemplarystructure of a three-layered wafer 3 with a single layer containing anactive substance 9 a.

The dosage form according to the invention is further elucidated by thefollowing examples.

EXAMPLE 1

The single-layered or multi-layered preparation according to the presentinvention preferably has a paper-like form.

The preparation according to the present invention dissolves preferablywithin 1 h, more preferably within 30 min, most preferably within 15 minand particularly most preferably within 5 min after contact with thesite of action, in particular the mucous membrane.

They essentially comprise a mucoadhesive, active substance containinglayer, which preferably comprises: mucoadhesive polymers such ascellulose derivatives, starch and starch derivatives, polyvinyl alcohol,polyethylene oxide, polyethylene, polypropylene, polyacrylic acid, andpolyacryl derivatives, polyvinylpyrrolidone, povidone, copovidone,sodium alginate, gelatin, xanthan gum, guar gum, carrageenan, pectins,dextrans, lectins, chitosan, pullulan, and mixtures thereof,plasticizers such as polyethylene glycol, glycerol, sorbitol, andmixtures thereof, and solvents such as water, ethanol, methanol,acetone, organic solvents, and mixtures thereof. Furthermore, additivessuch as colorants, fragrances, flavoring agents, preservatives,antioxidants, penetration enhancers, solubilizers, disintegrationaccelerators, lubricants, and mixtures thereof may be contained.

In particular, substances out of the following groups are suitable asactive pharmaceutical ingredients: drugs acting on the skeleton and themuscles, drugs acting on the nervous system, hormones and drugs actingon the hormonal system, gynecological acting drugs, drugs acting on thecardio-vascular system, drugs acting on the respiratory system, drugsacting on the gastrointestinal tract, diuretics, drugs acting on thesensory organs, dermatics, vitamins and micronutrients, peptide baseddrugs and proteins, analgesics, anti-infectives, and parasizides.

Development and Testing

In order to develop and test a preparation in the form of a wafersuitable for the present invention, testing methods based on thefollowing test and selection protocol 1 have been conducted.

In this way, preparations are obtained that meet the requirements whicharise, in particular, for a usage in connection with the dosage form.

In particular, the wafers according to the present invention aredistinguished over previously known wafers by the fact that they do notdissolve at just a slight contact with fluid already and that they havea relatively high stretchiness and fracture resistance.

Testing and Selection Protocol 1

Especially for a vaginal, rectal or intestinal mucous membrane, atensile strength of less than 3.5 MPa may be beneficial to increase thesafety, the user convenience and/or to enable a close but flexiblefitting of the sheet like preparation with the respective mucosa.

Especially for an esophageal mucous membrane and/or for the applicationto the esophagus, a tensile strength of more than 15 MPa may bebeneficial, particularly for avoiding a rupture of the sheet likepreparation during its application, especially during swallowing thedosage form.

EXAMPLE 2—SINGLE-LAYERED PREPARATION

Single-layered preparations, in particular wafers, that are suitable forthe usage according to the invention, may, in particular, comprise thefollowing formulations:

A 10%  PVA 20%  PEG 400 5% HPMC x% active pharmaceutical ingredient       ad 100% demineralized water B 5% PVA 15%  Kollicoat ® IR x%active pharmaceutical ingredient        ad 100% demineralized water or C5% PVA 15%  Kollicoat ® IR 8% Glycerol 85% x% active pharmaceuticalingredient        ad 100% demineralized water

EXAMPLE 3—TWO-LAYERED PREPARATION

Two-layered preparations, in particular wafers, according to the presentinvention comprise a mucoadhesive layer containing an active substanceand a water-impermeable layer, which is called a backing layer. Themucoadhesive layer containing an active substance is preferably composedof mucoadhesive polymers as cellulose derivates, starch and starchderivates, polyvinyl alcohol, polyethylene oxide, polyethylene,polypropylene, polyacrylic acid and polyacrylate derivates,polyvinylpyrollidone, Povidone, Copovidone, sodium alginate, gelatin,xanthan gum, guar gum, Carrageenan, pectins, dextrans, lectins,Chitosan, Pullulan an mixtures thereof, plasticizers such aspolyethylene glycol, glycerol, sorbitol and mixtures thereof, and thesolvent such as water, ethanol, methanol, acetone, organic solvents andmixtures thereof. Furthermore, additives such as colorants, fragrances,flavoring agents, preservatives, antioxidants, penetration enhancers,solubilizers, disintegration accelerators, lubricants, and mixturesthereof may be contained. Substances of the following group are suitableas active pharmaceutical ingredients: Drugs acting on the skeleton andon the muscles, drugs acting on the nervous system, hormones and drugsacting on the hormonal system, gynecological acting drugs, drugs actingon the cardio-vascular system, drugs acting on the respiratory system,drugs acting on the gastrointestinal tract, diuretics, drugs acting onthe sensory organs, dermatics, vitamins and micronutrients, peptidebased drugs and proteins, analgesics, anti-infectives and parasizides.

The backing layer preferably comprises an ethyl cellulose layer ofvarying thickness, wherein ethyl cellulose of different viscosities maybe used. Furthermore, it is possible to incorporate further additivessuch as colorants, fragrances, flavoring agents, preservatives,antioxidants, solubilizers, pore formers, lubricants, and mixturesthereof.

Table 1 which follows shows various exemplary compositions of layers ofa two-layered wafer 3 according to the present invention.

TABLE 1 Adhesive layer containing an active substance PVA 10% 10% 10%10% 10% PEG 400 20% 20% 20% 20% 20% HPMC  5%  5%  5%  5%  5% Activepharmaceutical  x%  x%  x%  x%  x% ingredients Water ad ad ad ad ad 100%100% 100% 100% 100% Water-impermeable layer (backing layer) Ethylcellulose 10 300 μg 400 μg 500 μg 750 μg 5000 μg (4% solution inacetone) EC/cm² EC/cm² EC/cm² EC/cm² EC/cm² Ethyl cellulose 45 300 μg400 μg 500 μg 750 μg 5000 μg (4% solution in acetone EC/cm² EC/cm²EC/cm² EC/cm² EC/cm²

The sheet-like, in particular film-shaped, foil-shaped, wafer-shapedpreparation 3 comprising the active pharmaceutical ingredient comprisesat least one first layer 9 a containing the active substance. The layer9 a containing the active substance preferably comprises a polymer, morepreferably a film-forming polymer, wherein the polymer fraction in thelayer 9 a containing the polymer and the active substance is 10 to 90%by weight, preferably 20 to 70% by weight, and more preferred 30 to 60%by weight, and wherein the layer containing the active substance, inparticular in a two-layered wafer, is an adhesive layer 9 a, and whereinthe polymer is a water-dispersible and/or water-decomposable and/orwater-disintegrable film-forming polymer.

Furthermore, the sheet-like, in particular film-shaped or wafer-shapedpreparation 3 comprising the active pharmaceutical ingredient comprisesat least one active substance free layer 9 c, that does not contain anactive pharmaceutical ingredient. In a three-layered wafer 3 the wafer 3comprises a further active substance-free layer 9 d that also does notcontain an active pharmaceutical ingredient. Such a first activesubstance free layer 9 c and/or such a further active substance freelayer 9 d is preferably a water-insoluble layer, e.g. made of orcomprising ethyl cellulose. An active substance free layer 9 c and/or afurther active substance free layer 9 d may be formed as an adhesivelayer, in particular in a two-layered wafer 3, wherein the layerconsists of or comprises e.g. hydroxypropyl methylcellulose. In amulti-layered, in particular three-layered wafer 3 layer 9 a containingthe active substance is preferably arranged between two active substancefree layers 9 c, 9 d., wherein a layer 9 a containing the activesubstance may be arranged between a first active substance free layer 9c and a further active substance free layer 9 d and wherein preferablythe first active substance free layer 9 c is a water-insoluble layer,which more preferably comprises ethyl cellulose, and wherein the atleast one further active substance-free layer 9 d is an adhesive layer,which more preferably comprises hydroxypropyl methylcellulose.

EXAMPLE 4—THREE-LAYERED PREPARATION

Three-layered preparations, in particular wafers, according to thepresent invention preferably comprise a mucoadhesive layer containing anactive substance, a water-impermeable layer, which is called a backinglayer, and an adhesive protective layer. The mucoadhesive layercontaining the active substance may be composed of mucoadhesive polymerssuch as cellulose derivatives, starch and starch derivatives, polyvinylalcohol, polyethylene oxide, polyethylene, polypropylene, polyacrylicacid, and polyacryl derivatives, polyvinylpyrrolidone, povidone,copovidone, sodium alginate, gelatin, xanthan gum, guar gum,carrageenan, pectins, dextrans, lectins, chitosan, pullulan, andmixtures thereof, plasticizers such as polyethylene glycol, glycerol,sorbitol, and mixtures thereof, and solvents such as water, ethanol,methanol, acetone, organic solvents, and mixtures thereof. Furthermore,additives such as colorants, fragrances, flavoring agents,preservatives, antioxidants, penetration enhancers, solubilizers,disintegration accelerators, lubricants, and mixtures thereof may becontained. In particular, substances out of the following groups aresuitable as active pharmaceutical ingredients: drugs acting on theskeleton and the muscles, drugs acting on the nervous system, hormonesand drugs acting on the hormonal system, gynecological acting drugs,drugs acting on the cardio-vascular system, drugs acting on therespiratory system, drugs acting on the gastrointestinal tract,diuretics, drugs acting on the sensory organs, dermatics, vitamins andmicronutrients, peptide based drugs and proteins, analgesics,anti-infectives, and parasizides. The backing layer is made of an ethylcellulose layer with a varying thickness, wherein ethyl cellulose withvarious viscosities may be used. Moreover, the incorporation of otheradditives such as colorants, fragrances, flavoring agents,preservatives, antioxidants, solubilizers, pore formers, lubricants, andmixtures thereof is possible. The adhesive protective layer may vary inits thickness and is made of mucoadhesive polymers such as cellulosederivatives, starch and starch derivatives, polyvinyl alcohol,polyethylene oxide, polyethylene, polypropylene, polyacrylic acid, andpolyacryl derivatives, polyvinylpyrrolidone, povidone, copovidone,sodium alginate, gelatin, xanthan gum, guar gum, carrageenan, pectins,dextrans, lectins, chitosan, pullulan, and mixtures thereof, and asolvent such as water, ethanol, methanol, acetone, organic solvents, andmixtures thereof. Furthermore, additives such as colorants, fragrances,flavoring agents, preservatives, antioxidants, penetration enhancers,solubilizers, disintegration accelerators, pore formers, lubricants, andmixtures thereof may be contained.

Table 2 which follows shows various exemplary compositions of layers ofsuch a three-layered wafer 3.

TABLE 2 Adhesive protective layer HPMC 50-100 50-100 50-100 50-100 (0.5%solution in water) μm μm μm μm layer layer layer layer Mucoadhesivelayer containing the active substance PVA 10% 10% 10% 10% PEG 400 20%20% 20% 20% HPMC  5%  5%  5%  5% Active pharmaceutical  x%  x%  x%  x%ingredients Water ad 100% ad 100% ad 100% ad 100% Water-impermeablelayer (backing layer) Ethyl cellulose 10 300 μg 400 μg 500 μg 750 μg (4%solution in acetone) EC/cm² EC/cm² EC/cm² EC/cm² Ethyl cellulose 45 300μg 400 μg 500 μg 750 μg (4% solution in acetone EC/cm² EC/cm² EC/cm²EC/cm²

A sheet-like preparation 3 of a pharmaceutical dosage form 1 accordingto the present invention may also be formed out of one layer or out ofmultiple layers, in particular out of two layers.

EXAMPLE 5 Regarding the Calculation of the Amount of Active IngredientPer Wafer:

In particular, the amount of active ingredient based on the layerthickness of the wet polymer film can be calculated according to thefollowing formula:

${m\left( {{active}\mspace{14mu} {pharmaceutical}\mspace{14mu} {ingredient}} \right)} - \frac{{m({formulation})}*{m\left( \frac{{active}\mspace{14mu} {pharmaceutical}\mspace{14mu} {ingredient}}{wafer} \right)}*10000}{{p\left( {{polylmer}\mspace{14mu} {mass}} \right)}*{A({wafer})}*{h\left( {{doctor}\mspace{14mu} {blade}} \right)}}$

whereinm mass [g]p density [g/cm³]A area [cm²]h height [μm]

In this context it is important to keep in mind that the height of thedoctor blade is not equal to the layer thickness of the wet wafer.Reasons for this are, for example, the shearing of the polymer filmwhile it is spread out, the flowing apart or flowing together of thepolymer composition after spreading out, and the formation of thickerregions at the edges of the polymer film. The extent of these processesis, inter alia, dependent on the viscosity of the polymer solution andon the used active pharmaceutical ingredient. Therefore, for each activepharmaceutical ingredient a specific individual fraction may be added tothe calculated amount of active ingredient. This additional fraction is

-   -   35% for sodium fluorescein    -   40% for quinine    -   35% for sodium diclofenac

Moreover, one may use a drug specific factor to adjust the calculatedamount, wherein, in particular, the drug specific factor is 100%+theadditional fraction, and therefore the formula reads:

${m\left( {{active}\mspace{14mu} {pharmaceutical}\mspace{14mu} {ingredient}} \right)} - {\frac{{m({formulation})}*{m\begin{pmatrix}{{active}\mspace{14mu} {pharmaceutical}\mspace{14mu} {ingredient}} \\{wafer}\end{pmatrix}}*10000}{{p\left( {{polylmer}\mspace{14mu} {mass}} \right)}*{A({wafer})}*{h\left( {{doctor}\mspace{14mu} {blade}} \right)}}*{drug}\mspace{14mu} {specific}\mspace{14mu} {factor}}$

EXAMPLE 6—MANUFACTURE OF SINGLE-LAYERED WAFERS

The manufacture of single-layered wafers is carried out by a solventcasting method, wherein at first all ingredients are dissolved in thesolvent, homogenized, and subsequently spread out on a suitable releaseliner to the desired thickness using a doctor blade. Then, the resultingfilm is dried under defined conditions and then cut into pieces ofsuitable size.

In the following, the manufacturing methods for the preparationsmentioned in Example 2 above are described in detail:

A At first, polyvinyl alcohol (PVA) is dissolved in demineralized waterin a beaker at a temperature of 90° C. and at a stirring speed of 400rpm. Then, polyethylene glycol 400 (PEG 400) and the medical substanceor the medical substance solution, respectively, is added and thesolution is homogenized. Finally, hydroxypropyl methylcellulose (HPMC)is added with stirring, homogenized, and the evaporation loss iscompensated with demineralized water. The polymer solution is coveredand left overnight and centrifuged on the next day at 4400 rpm for 50min in order to remove air bubbles. Then, the solution is evenly spreadout onto the release liner by means of a doctor blade and the polymerfilm is dried for 6 h at 40° C. in a drying cabinet. Before testing andfurther use, the film is cut into appropriately sized pieces anddetached from the release liner. The single-layered wafer is stored onthe release liner and is wrapped in aluminum foil.

B At first, polyvinyl alcohol (PVA) and Kollicoat® IR are dissolved indemineralized water in a beaker at a temperature of 90° C. and at astirring speed of 400 rpm. Then, the medical substance or the medicalsubstance solution, respectively, is added, homogenized, and theevaporation loss is compensated with demineralized water. The polymersolution is covered and left overnight and is centrifuged at 4400 rpmfor 15 min on the next day in order to remove air bubbles. Then, thepolymer solution is evenly spread out onto the release liner by means ofa doctor blade and the polymer film is dried for 5 h at 40° C. in adrying cabinet. Before testing and further use, the film is cut intoappropriately sized pieces and detached from the release liner. Thesingle-layered wafer is stored on the release liner and is wrapped inaluminum foil.

C At first, polyvinyl alcohol (PVA) and Kollicoat® IR are dissolved indemineralized water in a beaker at a temperature of 90° C. and at astirring speed of 400 rpm. Then, Glycerol 85% and the medical substanceor the medical substance solution, respectively, are added, homogenized,and the evaporation loss is compensated with demineralized water. Thepolymer solution is covered and left overnight and is centrifuged at4400 rpm for 15 min on the next day in order to remove air bubbles.Then, the polymer solution is evenly spread out onto the release linerby means of a doctor blade and the polymer film is dried for 5 h at 40°C. in a drying cabinet. Before testing and further use, the film is cutinto appropriately sized pieces and detached from the release liner. Thesingle-layered wafer is stored on the release liner and is wrapped inaluminum foil.

EXAMPLE 7—MANUFACTURE OF MULTI-LAYERED WAFERS

For the manufacturing of multi-layered wafers, like those mentioned inExample 3 and Example 4, the individual layers are initiallymanufactured by the solvent casting method. Therefore, all ingredientsof the layer are dissolved in the solvent, homogenized, and subsequentlyspread out to the desired thickness using a doctor blade. Then, theindividual layers are either spread out one above the other or jointtogether in various ways such as pressure or “gluing”. Thereafter, theresulting film is cut into pieces of appropriate size.

In the following, the manufacturing methods for the above-mentionedformulations of two- and three-layered wafers are described in detail:

Manufacture of Two-Layered Wafers:

1 At first, the polymer solution for the mucoadhesive layer containingthe active substance is manufactured according to “Manufacture ofSingle-layered Wafers A” and a 4% (w/v) ethyl cellulose solution ECsolution in acetone is prepared. Then, the EC solution is evenly sprayedonto the release liner with the desired layer thickness and dried atroom temperature for 15 min. Then, the polymer solution is evenly spreadout over it by means of the doctor blade and the resulting two-layeredfilm is dried at 40° C. for 6 h in a drying cabinet. Before testing andfurther use, the film is cut into appropriately sized pieces anddetached from the release liner. The two-layered wafer is stored on therelease liner and wrapped into aluminum foil.

2. At first, the polymer solution for the mucoadhesive, active substancecontaining layer is prepared according to “Manufacture of aSingle-layered Wafer A” and a 4% (w/v) EC solution in acetone isprepared. The, the polymer solution is evenly spread out onto therelease liner by means of a doctor blade and the polymer film is driedfor 4 h at 40° C. in a drying cabinet. Then, the EC solution is evenlysprayed onto the partly dried, still sticky polymer film in the desiredlayer thickness. Finally, the resulting two-layered film is, again,dried for 2 h at 40° C. in a drying cabinet such that both layers firmlyinterconnect. Before testing and further use, the film is cut intoappropriately sized pieces and pulled off the release liner. Thetwo-layered wafer is stored on the release liner and wrapped in aluminumfoil.

3. At first, the polymer solution for the mucoadhesive, active substancecontaining layer is prepared according to “Manufacture of aSingle-layered Wafer A” and a 4% (w/v) EC solution in acetone isprepared. Then, the polymer solution is evenly spread onto the releaseliner by means of a doctor blade and the polymer film is dried for 4 hat 40° C. in a drying cabinet. In parallel, the EC solution is evenlysprayed onto a second release liner in the desired layer thickness anddried for 15 min at room temperature. Then, the resulting EC film iscarefully detached from the release liner and is pressed onto the partlydried, still sticky polymer film by means of a roller. Finally, the nowtwo-layered film is dried for 2 h at 40° C. in a drying cabinet suchthat both layers firmly interconnect. Before testing and further use,the film is cut into appropriately sized pieces and detached from therelease liner. The two-layered wafer is stored on the release liner andwrapped in aluminum foil.

Manufacture of Three-Layered Wafers:

1. At first, the polymer solution for the mucoadhesive, active substancecontaining layer prepared according to “Manufacture of Single-layeredWafer A”, a 4% (w/v) EC solution in acetone, and a 0.5% (w/v) HPMCsolution in cold, demineralized water is prepared. Then, the EC solutionis evenly sprayed onto the release liner with a desired layer thicknessand dried for 15 min at room temperature. Then, the polymer solution isevenly spread out over it by means of a doctor blade and the resultingtwo-layered film is dried for 6 h at 40° C. in a drying cabinet.Finally, the HPMC solution is spread out over it as a third layer bymeans of a doctor blade and the resulting three-layered film is, onceagain, dried for 2 h at 40° C. in a drying cabinet such that all layersfirmly interconnect. Before testing and further use, the film is cutinto appropriately sized pieces and detached from the release liner. Thethree-layered wafer is stored on the release liner and wrapped intoaluminum foil.

2. At first, the polymer solution for the mucoadhesive layer containingthe active ingredient is prepared according to “Manufacture ofSingle-layered Wafers”, a 4% (w/v) EC solution in acetone is prepared,and a 0.5% (w/v) HPMC solution in cold, demineralized water is prepared.Then, the EC solution is evenly sprayed onto the release liner in thedesired layer thickness and dried for 15 min at room temperature. Then,the polymer solution is evenly spread out over it by means of a doctorblade and the resulting two-layered film is dried for 6 h at 40° C. in adrying cabinet. In parallel, the HPMC solution is spread out onto asecond release liner with their desired layer thickness and dried for 2h at 40° C. in a drying cabinet. Then, the HPMC film is carefully pulledoff the release liner and glued onto the two-layered film with water asbinder. Finally, the resulting two-layered film is dried for 1 h at 40°C. in a drying cabinet such that all layers firmly interconnect. Beforetesting and further use, the film is cut into appropriately sized piecesand pulled off the release liner. The three-layered wafer is stored onthe release liner and wrapped into aluminum foil.

3. At first, the polymer solution for the mucoadhesive, active substancecontaining layer is prepared according to “Manufacture of Single-layeredWafers A”, a 4% (w/v) EC solution in acetone is prepared, and a 0.5%(w/v) HPMC solution in cold, demineralized water is prepared. Then, thepolymer solution is evenly spread out onto the release liner by means ofa doctor blade and the polymer film is dried for 6 h at 40° C. in adrying cabinet. In parallel, the HPMC solution is spread out onto asecond release liner in the desired layer thickness and dried for 1 h at40° C. in a drying cabinet. Then, the resulting polymer film iscarefully pulled off the release liner and pressed onto the partlydried, still sticky HPMC film by means of a roller. Then, the nowtwo-layered film is dried for 1 h at 40° C. in a drying cabinet suchthat both layers firmly interconnect. Finally, the EC solution is evenlysprayed onto the two-layered film with a desired layer thickness and theresulting, three-layered film is dried for 30 min at room temperature.Before testing and further use, the film is cut into appropriately sizedpieces and pulled from the release liner. The three-layered wafer isstored on the release liner and wrapped into aluminum foil.

4. At first, the polymer solution for the mucoadhesive, active substancecontaining layer is prepared according to “Manufacture of Single-layeredWafers A”, a 4% (w/v) EC solution in acetone is prepared, and a 0.5%(w/v) HPMC solution in cold, demineralized water is prepared. Then, theHPMC solution is spread out onto the release liner with a desired layerthickness and dried for 2 h at 40° C. in a drying cabinet. Then, thepolymer solution is spread out over it by means of a doctor blade andthe resulting two-layered film is dried for 4 h at 40° C. in a dryingcabinet. In parallel, the EC solution is evenly sprayed onto a secondrelease liner in the desired thickness and dried for 15 min at roomtemperature. Subsequently, resulting EC film is carefully pulled off therelease liner and pressed onto the partly dried, still stickytwo-layered film by means of a roller. Finally, the now three-layeredfilm is dried for 2 h at 40° C. in a drying cabinet such that all layersfirmly interconnect. Before testing and further use, the film is cutinto appropriately sized pieces and pulled off the release liner. Thethree-layered wafer is stored on the release liner and wrapped intoaluminum foil.

The features of the present invention disclosed in the descriptionabove, in the claims, and in the drawings can be essential bothindividually and also in any combination for implementing the inventionin its various embodiments.

In FIG. 8a a schematic illustration of the pharmaceutical dosage form 1according to the invention in accordance with a fourth embodiment of theinvention is shown. In particular, this illustration shows thepharmaceutical dosage form 1, wherein the sheet like preparation 3 is ina compact form. Moreover, without limiting the scope of this example,FIG. 8a shows the pharmaceutical dosage form 1 as a side view. A part ofthe sheet like preparation 3 is a rolled around a rod 19. This roll ofthe sheet like preparation 3 and the rod 19 together with the elongatedpart of the sheet like preparation 3 form the release mechanism. It isto be understood, that in some variants of the fourth embodiment the rod19 is not necessary for the release mechanism 4, and thus omitted. Theshell 2 contains the release mechanism 4 in the inner space 7 of theshell 2. Thus, the sheet like preparation 3 and the release mechanismform is protected. Preferably, the shell 2 is formed as a capsule. Thiscapsule 2 facilitates swallowing the dosage form or, in particular, thepart of the dosage form that have to be swallowed for the desiredapplication. Furthermore, the shell 2 comprises an aperture 6, throughwhich the sheet like preparation 3 may leave the shell 2. It is to beunderstood, that also the aperture 6 may be regarded as a part of therelease mechanism 4 as it facilitates the release of the sheet likepreparation 3. The trigger mechanism 5 is connected to the sheet likepreparation 3 and is outside the shell 2. It is to be understood, that apart of the trigger mechanism 5 may be inside the shell 2 and/or that apart of the sheet like preparation 3 may be outside the shell 2.Moreover, the trigger mechanism 5 may be formed by a sophisticated partof the sheet like preparation 3. Additionally, the shell 2 comprises asealing 18 that seals the aperture 6, at least in an initial state ofthe dosage form 1, in particular in a state of the dosage 1 that isparticularly suited for storage. Such a manner, the inner space of theshell 7 may be protected from the environment such as humidity, liquidsor microbes.

Especially, the fourth embodiment relates to an orally administrabledosage form for the treatment of the esophageal mucosa. In this case, itcan deliver useful substances such as an active pharmaceuticalingredient to the esophageal mucous membrane by unrolling its sheet likepreparation 3 while moving along the esophagus when it is swallowed.Thus, active pharmaceutical ingredients contained in the sheet likepreparation 3 can be locally released to the mucous membrane of theesophagus. Current treatments for local diseases of the esophagusgenerally employ swallowing the content of application systems, whichwere designed for inhalation therapy of the lung, or swallowing a gelcontaining specific drugs. However, generally the swallowed content ofthe application systems or the gel only has a short contact time withthe esophageal mucosa. Therefore, the local effect is decreased and thesystemic effect is increased, in particular, compared to an applicationform, in which the contact time is prolonged. By applying the sheet likepreparation 3 to the esophageal mucosa a pharmaceutical dosage form 1according to the fourth embodiment of the invention the treatment oflocal diseases of the esophagus can be improved and, in particular, thecontact time can be prolonged. When applied to the esophageal mucosa,the sheet like preparation 3 stays in contact with the mucosa whilstproviding a controlled release of the active pharmaceutical ingredientin order to achieve a local therapy or diagnosis. Preferably, thecontrolled release can neither be immediate, sustained or prolonged,also preferably, during or after the release of the activepharmaceutical ingredient or the active pharmaceutical ingredients thesheet like preparation 3 dissolves and is, preferably swallowed.Moreover, the shell 2 may detach from the sheet like preparation 3immediately after the release of the sheet like preparation 3 or maydissolve while still attached to the sheet like preparation 3.Preferably, the shell 2 is made of a dissolvable and/or digestiblematerial. Moreover, the trigger mechanism 5 is a holding device 5. Inparticular, the holding device 5 is adapted to be fixed in the oralcavity. Therefore, the holding device 5 has a mucoadhesive surface,preferably comprising cellulose derivates, starch and starch derivates,polyvinyl alcohol, polyethylene oxide, polyethylene, polypropylene,polyacrylic acid and polyacrylate derivates, polyvinylpyrollidone,Povidone, Copovidone, sodium alginate, gelatin, xanthan gum, guar gum,Carrageenan, pectins, dextrans, lectins, Chitosan, Pullulan an mixturesthereof. So, preferably, the holding device 5 can be attached to theoral mucosa, in particular the buccal mucosa, i.e. the inside of thecheek.

Even more specifically, the fourth embodiment of the invention may referto a pharmaceutical dosage form for the treatment of eosinophilicesophagitis. Eosinophilic esophagitis is an inflammatory,immune-mediated disease with increasing relevance in gastrointestinaldisorders. This disease can be treated with topic steroids. Preferably,the shell 2 is a capsule made out of hard gelatin. In an initial stateof the dosage form 1, the sheet like preparation 3 is in a compact form,in particular in form of a coil, and is connected to the triggermechanism 5. The trigger mechanism 5 is a holding device 5 as describedabove. On administration, the holding device is attached in the oralcavity, preferably to the buccal mucosa, in particular by gluing it tothe mucosa. Next, the dosage form 1 is swallowed, preferably with abeverage or water, and, therefore, the dosage form 1 moves along theesophagus and a force acts on the holding device 5 triggering therelease of the sheet like preparation 3 by the release mechanism 4.While the dosage form 1 moves down the esophagus the sheet likepreparation 3 is unrolled, and thus released. Preferably, the sheet likepreparation is mucoadhesive, and thus may adhere to the mucous membraneof the esophagus. In this case, the contact and/or position of the sheetlike preparation is not or is not only dependent on the holding device5. Afterwards, an oblong region of the esophageal mucosa is covered orat least near to the sheet like preparation 3. Thus, it can be treatedwith active pharmaceutical ingredients, in particular topic steroids,released by the sheet like preparation 3. Preferably, the sheet likepreparation 3 may comprise and release fluticasone or budesonide.

Preferably, the manufacture of a sheet like preparation 3, in particularaccording to the fourth embodiment of the present invention, is carriedout by a solvent casting method, wherein at first all ingredients aredissolved in the solvent, homogenized, and subsequently spread out on asuitable release liner to the desired thickness using a doctor blade.Then, the resulting film is dried under defined conditions and then cutinto pieces of suitable size.

In a preferred variant, the ingredients, particularly the polymermatrix, consists of 10% m/m polyvinyl alcohol (PVA) (Mowiol 40-88)suspended in a 20% m/m Kollicoat IR aqueous solution. Furthermore, theactive pharmaceutical ingredient such as fluticasone or budesonide aswell as additives such as methylene blue as a visual control is added.

A sheet like preparation 3 manufactured according to this preferredvariant has been experimentally analyzed. For this purpose the sheetlike preparation 3 was tested for film thickness and uniformity of mass.Furthermore, disintegration time was tested both and purified water andon wetted are alginate gel (3% m/m) to simulate the mucosa. Fullydisintegration was defined as the absence of any solid matrix particle.Tensile strength, elongation and extraction force have been measuredusing a texture analyzer. All tests were performed triplicate and meanplus/minus standard derivation are reported. The resulting sheet likepreparation 3 had a thickness of 114±5 μm and a mean mass of 9.39±0.03mg/cm². The disintegration time in water was 760±35 s, and greater than1200 s on alginate gel. The tensile strength was 31.35 MPa. Theelongation at break was 7.41±0.90%.

Preferably, a pharmaceutical dosage form 1, in particular according tothe fourth embodiment of the present invention, may be manufactured asdescribed in the following:

-   -   cutting the film resulting from a solvent casting technique to        strips of 400 mm by 4 mm;    -   folding or rolling the resultant sheet like preparations 3;    -   providing a hard gelatin capsule of size 1 is a shell 2;    -   cutting an aperture 6 into a part of the hard gelatin capsule 2,        specifically, as illustrated, into the upper part;    -   threading one end of the sheet like preparation 3 through the        aperture 6; and    -   closing the capsule 2.

Here, the trigger mechanism, in particular holding device 5, is formedby the part of the sheet like preparation 3 that is outside the shell 2and the release mechanism 4 is formed by the part of the sheet likepreparation 3 that is inside the shell 2, and preferably the aperture 6.

A dosage form 1 manufactured as described above comprising the preferredvariant of the sheet like preparation 3, in particular for the fourthembodiment of the present invention, has been experimentally analyzed,as described above. The extraction force of the sheet like preparation 3from the capsule 2 was 0.31±0.09 N in case of the rolled sheet likepreparation 3, and 0.24±0.45 N in case of the folded sheet likepreparation 3.

In FIG. 8b a schematic illustration of the pharmaceutical dosage form 1according to the invention in accordance with the fourth embodiment ofthe invention is shown. In particular, this illustration shows thepharmaceutical dosage form 1, wherein the sheet like preparation 3 is,at least partially, in an expanded form. Moreover, without limiting thescope of this example, FIG. 8b shows the pharmaceutical dosage form 1 isa top view. The shell 2 contains a rod 19 and a part of the sheet likepreparation 3 that is still rolled or coiled, which form the releasemechanism 4. The sheet like preparation 3 leaves the shell 2 through theaperture 6. In particular, it is unrolled within the shell 2, i.e. inthe inner space of the shell 7, and then elongates into the direction ofthe aperture 6.

Furthermore, the sheet like preparation 3 is divided into two regions, afirst region of the sheet like preparation 3 a and a second region ofthe sheet like preparation 3 b. The first region 3 a and the secondregion 3 b may comprise different active pharmaceutical ingredients.Preferably, the first region 3 a can comprise local anesthetics such asbenzocaine, butamben, dibucaine, lidocaine, oxybuprocaine or novocaine,and the second region 3 b can comprise a steroid such ascorticosteroids, glucocorticoids, fluticasone, budesonide orclocortolone. In particular, in this way, when treating the esophagus, agag reflex can be suppressed by the local anesthetic and the esophagealmucous membrane can be treated with the steroid. Additionally, the firstregion 3 a has a smaller cross-sectional area than the second region 3b. In particular, this beneficially facilitates swallowing the dosageform.

Furthermore, the holding device 5 is connected to the sheet likepreparation 3 or is a broadened part of the sheet like preparation 3with a mucoadhesive layer preferably comprising: mucoadhesive polymerssuch as cellulose derivatives, starch and starch derivatives, sodiumalginate, gelatin, xanthan gum, guar gum, carrageenan, pectins,dextrans, lectins, and mixtures thereof.

Additionally, the movement path PM of the dosage form 1 is illustrated.

Preferably, the preparation 3 is manufactured according to onemanufacturing method described in here. In particular, the sheet likepreparation with multiple regions, especially at least a first region 3a and at least a second region 3 b, can be manufactured similarly to amulti-layered preparation, wherein, at least some of, the layers areoffset to each other but still partially overlap. Also the holdingdevice 5 may be manufactured and/or connected to the sheet likepreparation 3 in this way.

FIG. 8c illustrates the enveloping cross-sectional areas of the fourthembodiment of the invention. The pharmaceutical dosage form 1, inparticular the shell 2, and the sheet like preparation 3, in particularthe portion of the sheet like preparation 3 that just has been releasede.g. a portion of the region 3 b, are shown as they viewed in thedirection of the movement path. Thus, the movement path in FIG. 8cpoints into the drawing area. As illustrated, the envelopingcross-sectional area of the dosage form AD is larger than the envelopingcross-sectional area of the released part of the sheet like preparationAP. In particular, this facilitates swallowing an orally administrablepharmaceutical dosage form 1.

In particular, the FIGS. 8a, b, and c have the same scale. It is to beunderstood, that the sheet like preparation 3 may be broader or narrowerrelative to the capsule 2 than illustrated. Preferably, the sheet likepreparation may be broader to better utilize the inner space of theshell 7. Alternatively, the sheet like preparation may be rolled,wherein some windings of the sheet like preparation 3 are beneficiallyoffset to each other. Thus, in particular, the inner space 7 is used ina more efficient way. Also preferably, the sheet like preparation 3 canform or can be comprises by a string member that is rolled or coiled. Inparticular, such a string member can be coiled in an efficient, reliableand/or space efficient way.

LIST OF REFERENCE SYMBOLS

-   -   1 pharmaceutical dosage form    -   2 shell    -   3 sheet like preparation    -   3 a, 3 b regions of the sheet like preparation, in particular        first and second region    -   4 release mechanism    -   5 trigger mechanism    -   6 aperture    -   7 inner space of the shell    -   8 predetermined breaking point    -   9 layer    -   9 a, 9 b layer containing an active substance    -   9 c, 9 d active substance free layer    -   10 spring element    -   11 first tube element    -   12 further tube element    -   13 first joint element    -   14 further joint element    -   15 central aperture of the wafer balloon    -   16 slit    -   17 cladding or shell parts    -   18 sealing    -   19 rod    -   PM movement path    -   AD enveloping cross-sectional area of the dosage form    -   AP enveloping cross-sectional area of the released part of the        sheet like preparation

1. A pharmaceutical dosage form (1) for the application to a mucousmembrane, in particular to a buccal, intestinal, rectal or vaginalmucous membrane, comprising at least one sheet like, in particular filmshaped, foil shaped or wafer shaped, preparation (3) comprising theactive pharmaceutical ingredient, a release mechanism (4) and a triggermechanism (5), wherein the trigger mechanism (5) is adapted to trigger,at a predetermined site of action, in particular of the gastrointestinaltract, of the rectum or of the vagina, the release of the sheet likepreparation (3) by the release mechanism (4).
 2. A pharmaceutical dosageform (1) according to claim 1, wherein the pharmaceutical dosage form(1) further comprises a shell (2), wherein the shell (2) contains atleast one sheet like, in particular film shaped, foil shaped or wafershaped, preparation (3) comprising the active pharmaceutical ingredient,and wherein preferably the shell (2) or the trigger mechanism (5)comprises at least one aperture (6) through which a fluid surroundingthe shell (2) can come into contact with the inner space (7) of theshell (2), wherein preferably the aperture (6) is formed as a slitand/or the aperture (6) is at least partially covered by the triggermechanism (5).
 3. A pharmaceutical dosage form (1) according to one ofthe claims 1 to 2, wherein the trigger mechanism (5) is adapted totrigger the release of the sheet like preparation (3) by the releasemechanism (4) after a contact of the pharmaceutical dosage form (1), inparticular of the trigger mechanism (5), with a key stimulus and/or thetrigger mechanism (5) is adapted to trigger the release of the sheetlike preparation (3) by the release mechanism (4) in a time controlledmanner or immediately and/or the release mechanism (4) is adapted torelease the sheet like preparation (3) in a time controlled manner orimmediately after triggering of the trigger mechanism (5).
 4. Apharmaceutical dosage form (1) according to one of the claims 1 to 3,wherein the release mechanism (4) is an expansion mechanism (4), whereinpreferably the expansion mechanism (4) is selected from the groupcomprising mechanical expansion system, gas driven expansion system,compressed foam or compressed tissue, and wherein more preferably anexpansion of the expansion mechanism (4) results in an opening of theshell (2).
 5. A pharmaceutical dosage form (1) according to one of theclaims 1 to 4, preferably claim 4, wherein the dosage form (1) containsthe preparation (3) in a folded form and, preferably, the expansion ofthe expansion mechanism (4) results in an unfolding of the preparation(3).
 6. A pharmaceutical dosage form (1) according to one of the claims1 to 5, wherein the shell (2) contains a gas-forming agent as therelease mechanism (4), in particular as the expansion mechanism (4), andthe gas-forming agent is arranged in a part of the shell (2) that isopposed to the part of the shell (2) containing the preparation (3). 7.A pharmaceutical dosage form (1) according to one of the claims 1 to 6,wherein the shell (2), in particular the expansion mechanism (4),preferably mechanical expansion system, comprises at least a first jointor lever element (13), preferably a hinge, and/or wherein the shell (2),in particular the expansion mechanism (4), preferably mechanicalexpansion system, comprises at least one spring element (10).
 8. Apharmaceutical dosage form (1) according to one of the claims 1 to 7,wherein the preparation (3) comprises a swelling agent (11) wherein theswelling agent (11) is preferably selected from the group comprisingsponge and fibers.
 9. A pharmaceutical dosage form (1) according to oneof the claims 1 to 8, wherein the shell (2) at least comprises a firsttube element (11), and preferably the shell (2) at least comprises afurther tube element (12), wherein preferably the second tube element(12) has a smaller tube diameter than the first tube element (11), andwherein preferably the second tube element (12) is arranged at leastpartially in the first tube element (11), and preferably the shell (2)further comprises a spring element (10), preferably a compressionspring, wherein the spring element (10) is arranged such that the springelement (10) can move the at least one second tube element (12)longitudinally relative to the first tube element (11).
 10. Apharmaceutical dosage form (1) according to one of the claims 1 to 9,wherein the shell (2), in particular the expansion mechanism (4),comprises at least a joint or lever element (13), and wherein preferablythe shell (2), in particular the expansion mechanism (4), preferablymechanical expansion system, comprises at least a further joint or leverelement (14), wherein preferably the first joint or lever element (13)and/or the further joint or lever element (14) is arranged at a free endof the shell (2).
 11. A pharmaceutical dosage form (1) according to oneof the claims 1 to 10, wherein the first joint or lever element (13)and/or the further joint or lever element (14) is at least partiallycovered by the trigger mechanism (5) and/or wherein the at least onefirst joint or lever element (13) or the at least one further joint orlever element (14) is arranged such that a joint or lever element (13,14), in particular lever, of one end is arranged adjacent to arespective joint or lever element, in particular lever, of the otherend.
 12. A pharmaceutical dosage form (1) according to one of the claims1 to 11, wherein: the sheet like preparation (3) provides, after itsrelease by the release mechanism (4), a relatively large surface area,and preferably comes into contact with a relatively large surface area;and/or the release mechanism (4) is adapted to release, at leastpartially, the sheet-like preparation (3) while moving along the mucousmembrane.
 13. A pharmaceutical dosage form (1) according to one of theclaims 1 to 5 or claim 12, wherein: the release mechanism (4) comprisesa string member (3); the string member (3) being expandable from acompact form, preferably a folded, collapsed, rolled or coiled up form,to an expanded form, preferably an unfolded, spread out, opened up,elongated, stretched, unrolled or oblong form, upon activation of therelease mechanism (4); and the string member comprises, at least in thecompact form, the sheet like preparation (3).
 14. A pharmaceuticaldosage form (1) according to one of the claims 1 to 5 or one of theclaims 12 to 13, wherein: the release mechanism (4) is an expansionmechanism (4), preferably elongation mechanism (4), adapted to expand,preferably unfold, elongate, uncoil, unroll or unwind, the sheet likepreparation (3) by leveraging an external movement, force or pressure.15. A pharmaceutical dosage form (1) according to one of the claims 1 to5 or one of the claims 12 to 14, wherein the trigger mechanism (5) is aholding device (5) that is a part of or is attached to the sheet likepreparation (3).
 16. A pharmaceutical dosage form (1) according to oneof the claims 1 to 5 or one of the claims 12 to 15, in particular forthe oral administration, wherein the trigger mechanism (5), inparticular the holding device (5), is adapted to be fixed in an oralcavity, preferably to a tooth, to a tongue, to a lip or to an oralmucous membrane, and/or to be held in a hand during administration, inparticular swallowing, of the pharmaceutical dosage form (1).
 17. Apharmaceutical dosage form (1) according to one of the claims 1 to 16,in particular for the oral administration, wherein, at least during therelease of the sheet like preparation (3), the released portion of thesheet-like preparation (3) and the dosage form (1) move relatively toeach other thereby defining a movement path (PM) of the dosage form (1),and the enveloping cross-sectional area (AD) of the dosage form (1), inparticular of a swallowable part of the dosage form (1), preferably theshell (2), viewed in the direction of the movement path is larger thanthe enveloping cross-sectional area (AP) of the released part of thesheet like preparation (3).